Leadership

Drew Weissman, M.D., Ph.D.

Director
Lab Website

Contact Information

1 uCity Square
25 N 38th St, 4^th Floor
Philadelphia, PA 19104

About

Drew Weissman, MD, PhD, is a world-renowned physician and researcher at Penn Medicine, best known for his contributions to RNA biology and the COVID-19 vaccines. He and co-collaborator Katalin Karikó, PhD, invented the modified mRNA technology being used in Pfizer-BioNTech and Moderna’s vaccines to prevent COVID-19.

More than 15 years ago at Penn Medicine, Weissman and Karikó found a way to modify mRNA and later developed a delivery technique to package the mRNA in fat droplets called lipid nanoparticles. This ensured that it could reach the proper part of the body and trigger the immune system to fight disease.

These laboratory breakthroughs made mRNA safe, effective, and practical for use as a vaccine against COVID. The Pfizer-BioNTech COVID-19 vaccine received FDA approval in August 2021, and the Moderna COVID-19 vaccine has been authorized by the FDA for emergency use.

Dr. Weissman and his team are currently at work on a pan-coronavirus vaccine to stop the next coronavirus epidemic, a universal flu vaccine, and a vaccine to prevent herpes. They are working with Penn colleagues to develop cancer therapeutics with mRNA technology. Weissman’s lab is also developing a SARS-CoV-2 mRNA vaccine with Chulalongkorn University in Thailand to help residents of Thailand and other surrounding nations with fewer financial resources than the United States access lifesaving vaccines.

Before joining Penn in 1997, Weissman was a fellow at the National Institutes of Health studying HIV in the lab of Dr. Anthony Fauci. Weissman received his bachelor’s degree and master’s degree from Brandeis University. He earned his MD and PhD from Boston University and completed his residency at Beth Israel Hospital.

Read a Q&A with Dr. Weissman about mRNA vaccines

Expertise

Programs and Centers

Penn Medicine’s programs and centers combine doctors from many disciplines to coordinate care from start to finish. Dr. Weissman is part of these programs:

• Penn Infectious Diseases Program

Education and Training

MEDICAL SCHOOL

Boston University School of Medicine

RESIDENCY

Beth Israel Deaconess Medical Center

FELLOWSHIP

National Institutes of Health

Latest from Dr. Weissman

Related Links

• Read a Q&A with Dr. Weissman about mRNA vaccines
• Immunology Graduate Group Faculty Profile
• CureTalks@Penn Research Interviews: Understanding mRNA Covid-19 Vaccines

Research

Description of Research Expertise

Dr. Weissman’s laboratory focuses on the study of RNA and innate immune system biology and the application of these findings to vaccine research and gene therapy. There are three main projects in his laboratory. The first project began through the use of mRNA encoding antigen as a delivery system to load dendritic cells to promote broad immune responses as part of a vaccine. This project has expanded to include basic studies of RNA immunogenicity and translation and the development of applications for gene therapy. The second project develops new HIV envelope immunogens that can induce broad responses and cross-reactive neutralizing antibodies. The third project continues previous studies that identified a protein found on DC, macrophages, and epithelial cells that binds HIV envelope with high affinity. The main focus of this project is testing whether this and related molecules function in vivo to promote HIV genital tract infection.

Memberships

• American Academy of Arts and Sciences, International
• American Federation for Clinical Research, National
• Association of American Physicians, National
• The American Association of Immunologists, National

Scientific Groups

• mRNA Core

James Hoxie, M.D.

Co-Director
Faculty Profile Page

Contact Information

1 uCity Square
25 N 38th St, 4^th Floor
Philadelphia, PA 19104
Room #4030

Publications

Search PubMed For Articles

Education:

B.A. Wesleyan University, 1972. M.D. University Of Pennsylvania, 1976.

Description of Research Expertise

Research Interests
Viral and cellular aspects of HIV (human immunodeficiency virus) and SIV (simian immunodeficiency virus) entry into cells; HIV and SIV pathogenesis; mechanisms of viral resistance to the host immune response; neutralizing antibodies; gene therapy of HIV infection.

Key words: AIDS, CD4, chemokine receptors, HIV, SIV, envelope glycoproteins, viral entry, neutralization, vaccine, vaccines, pathogenesis

Description of Research
Research in Dr. Hoxie’s lab is focused on identifying viral and cellular determinants that are relevant to the ability of HIV and SIV to infect cells and to evade host immune responses. Four specific areas of work include:

1. The role of the HIV/SIV cytoplasmic tail in pathogenesis. Dr. Hoxie’s group has identified endocytosis signals in the cytoplasmic tails of HIV, SIV and FIV Env proteins that reduce Env expression on the surface of infected cells. Dr. Hoxie has proposed that these signals could be relevant in pathogenesis by enabling virus-producing cells to survive host anti-viral immune responses. He has shown in an SIV model that viruses with mutations in this domain are markedly attenuated in vivo and controllable by host immune responses. Ongoing studies are addressing the mechanism for this attenuation, the components of the host immune response that are involved, and defects in viral assembly that are believed to underlie this effect. Additional studies are focusing on translating this project to SHIV viruses containing an HIV-1 envelope to determine if analogous mutations in their cytoplasmic tails can also lead to broadly protective immunity.
2. Studies of CD4-independent isolates of HIV. Dr. Hoxie has described CD4-independent isolates of HIV-1 and HIV-2 that can infect cells using chemokine receptors without CD4. His lab has shown that the genetic basis for this phenotype results from mutations that expose the chemokine receptor binding site on gp120. Efforts are in progress to identify the structural basis for this effect and to use CD4-independent envelope glycoproteins as HIV vaccine candidates. In addition, novel simian immunodeficiency viruses have been generated that lack a CD4 binding site to explore the consequences of CD4 tropism on pathogenesis and host immune responses. Additional studies are focusing on translating this project to novel SHIV viruses containing an HIV-1 envelope for evaluation in nonhuman primates.
3. Producing modified HIV envelope glycoproteins for vaccine studies. This work is directed towards deriving HIV envelope glycoproteins that can elicit broadly neutralizing antibodies. Current approaches are deriving viruses lacking structures that are believed to shield the envelope from humoral immune responses.
4. Gene therapy approaches using a fusion inhibitory peptide from the HIV-1 gp41 envelope molecule conjugated to the human chemokine receptor CXCR4. Published studies have shown that this molecule is potent and broad inhibitor of HIV-1 entry. Studies in the Hoxie lab are focusing on understanding the mechanism for this effect and exploring ways in which viral resistance to this inhibitor can occur. The modified CXCR4 inhibitory protein (termed C34-CXCR4) is currently being evaluated in human trials and the Hoxie lab is currently assessing whether subjects receiving autologous T cells that express this protein, produce antibodies to the C34-CXCR4 protein).

Rotation Projects

• Structure function studies of envelope glycoproteins focusing on mechanisms of CD4 and chemokine receptor engagement. Modulation of Envelope glycoproteins for the design of immunogens that can elicit broadly neutralizing antibodies.
• The role of the HIV/SIV cytoplasmic tail in pathogenesis.
• Studies evaluating mechanisms of neutralization sensitivity and resistance to antibodies.

Lab personnel:
Research Specialists:
Beth Haggarty
Josephine Romano

Students:
Son Nguyen

Research Investigator:
George Leslie

Description of Clinical Expertise

Hematologic malignancies
Allogeneic stem cell and bone marrow transplantation
HIV/AIDS

Selected Publications

Nolan KM, Jordan AP, and Hoxie JA: Effects of partial deletions within the HIV-1 V3 loop on coreceptor tropism and sensitivity to entry inhibitors. J. Virology 82(2): 664-73, January 2008.

Lin G, Bertolotti-Ciarlet A, Haggarty B, Romano J, Nolan KM, Leslie GJ, Jordan AP, Huang CC, Kwong PD, Doms RW, Hoxie J: Replication-competent variants of human immunodeficiency virus type 2 lacking the V3 loop exhibit resistance to chemokine receptor antagonists. J. Virology 81(18): 9956-66, September 2007.

Laakso MM, Lee FH, Haggarty B, Agrawal C, Nolan KM, Biscone M, Romano J, Jordan AP, Leslie GJ, Meissner EG, Su L, Hoxie JA, Doms RW: V3 loop truncations in HIV-1 envelope impart resistance to coreceptor inhibitors and enhanced sensitivity to neutralizing antibodies. PLoS Pathogens 3(8): e117, August 2007.

Fernando K, Hu H, Ni H, Hoxie JA, Weissman D: Vaccine-delivered HIV envelope inhibits CD4(+) T-cell activation, a mechanism for poor HIV vaccine responses. Blood 9(6): 2538-44, March 2007.

Byland R, Vance PJ, Hoxie JA, Marsh M: A conserved dileucine motif mediates clathrin and AP-2-dependent endocytosis of the HIV-1 envelope protein. Mol. Biol Cell 18(2): 414-25, February 2007.

Chaipan C, Soilleux EJ, Simpson P, Hofmann H, Gramberg T, Marzi A, Geier M, Stewart EA, Eisemann J, Steinkasserer A, Suzuki-Inoue K, Fuller GL, Pearce AC, Watson SP, Hoxie JA, Baribaud F, Pohlmann S: DC-SIGN and CLEC-2 mediate human immunodeficiency virus type 1 capture by platelets. J. Virology 80(18): 8951-60, September 2006.

Wei Q, Stallworth JW, Vance PJ, Hoxie JA, Fultz PN: Simian immunodeficiency virus (SIV)/immunoglobulin G immune complexes in SIV-infected macaques block detection of CD16 but not cytolytic activity of natural killer cells. Clin. Vaccine Immunology 13(7): 768-78, July 2006.

Mohamad-Gabriel Alameh, Ph.D.

Co-Director of the mRNA Core

University of Pennsylvania
380 S. University Ave
Vernon and Shirley Hill Pavilion
University of Pennsylvania
Philadelphia, PA 19104

Dr. Alameh received his B.S. and M.S. degrees from the University of Montreal, and his Ph.D. in Biomedical Engineering from Polytechnique Montreal. His thesis work focused on understanding the intrinsic and extrinsic parameters affecting chitosan-siRNA nanoparticle macromolecular properties and their effect on in vitro, and in vivo efficacy; a work that has led to better understanding of chitosan-nucleic acid design principles. Dr. Alameh joined the laboratory of Dr. Drew Weissman at the University of Pennsylvania as a Postdoctoral Fellow in 2018, where he leads multiple vaccine projects as well as projects to better understand the interaction of lipid nanoparticles with the immune system. Dr. Alameh is also involved in the development of novel proprietary lipids, adjuvants and display strong interest in mRNA construct optimization.

Dr. Alameh is also the director of the Engineered mRNA and Targeted Nanomedicine Core.

Scientific Groups

• mRNA Core

Montserrat Anguera, Ph.D.

Non-coding RNA Group Lead
Lab Website

Contact Information

University of Pennsylvania
School of Veterinary Medicine
3800 Spruce Street
Philadelphia, PA 19104
Tel: 215-898-0567
Fax: 215-573-6810
Email: anguera@vet.upenn.edu

Research Areas: Epigenetics, X-Chromosome Inactivation, Xist RNA, female-biased autoimmunity, epigenetic analyses using female lymphocytes, allele-specific analyses, RNA/DNA FISH, microscopy, long noncoding RNAs
PubMed Link

Research

RESEARCH INTERESTS:
The research in the Anguera laboratory focuses on maintenance of X-chromosome Inactivation in the immune system and in stem cells. They also study epigenetic mechanisms involving long noncoding RNAs during early human development and placental progenitors.

RESEARCH AREAS:
Mechanisms of X-chromosome Inactivation:
We are investigating the molecular mechanisms of X-Chromosome Inactivation, and how altered dosage of X-linked genes affects early embryonic development and contributes to sex-biased disease. We focus on the autoimmune disorder lupus, which has a strong female-bias, exhibits overexpression of X-linked immune-related genes, and involves lymphocytes. We study the epigenetic status of the inactive X in female lymphocytes from humans and mice, and have made the remarkable discovery that these cells do not maintain X-Chromosome Inactivation in the same way as other female somatic cells. We were the first to discover that the inactive X has euchromatic features in female lymphocytes, which may explain the female bias in autoimmune disorders such as lupus. We also study the dynamic mechanisms of Xist RNA localization and heterochromatin mark recruitment to the inactive X following lymphocyte activation.

Long noncoding RNAs during early human development:
We are also investigating sex-specific differences during human placental development using in vitro model systems. We discovered a novel X-linked long noncoding RNA specifically expressed in human placental progenitor cells that regulates the innate immune response.

KEY WORDS
X-chromosome Inactivation, Xist RNA, epigenetics, heterochromatin, female-biased autoimmunity, B cell development, B cell quiescence and activation, T cell quiescence and activation.

Education

Ph.D (Biochemistry, Molecular and Cellular Biology) Cornell University, 2004

Training

Massachusetts General Hospital / Harvard Medical School (2004 to 2012)
Fellow in Molecular Biology

Scientific Groups

• Non-coding RNA

Yoseph Barash, Ph.D.

RNA Processing Group Lead
Lab Website

Publications

Contact Information

University of Pennsylvania
Richards Building D205
3700 Hamilton Walk
Philadelphia, PA 19104

Bio

Yoseph Barash is a computational biologist who works on predictive models to understand RNA biogenesis, its regulation, and its role in human disease. His lab, the BioCiphers lab, develops machine learning algorithms that integrate genomic and genetic data, followed by wet lab experimental verifications. In recent years the lab has also grown to work in the space of technology development, creating new high-throughput assays. Yoseph earned a B.Sc. in Physics and Computer Science at the Hebrew University, and worked at a start-up as a programmer and algorithm developer. He then continued to earn a Ph.D. in machine learning under Prof. Nir Friedman at the Hebrew University (2006). Following that, Yoseph did his postdoctoral work with Prof. Ben Blencowe and Prof. Brendan Frey at the University of Toronto, focusing on alternative splicing of RNA. His work was the first to build predictive models for splicing variations as a function of the cellular condition (Barash et al Nature 2010), later extended to genetic variations (Xiong et al Science 2015). In 2012 Yoseph moved to the University of Pennsylvania as an Assistant Professor in the Department of Genetics in the Medical school, and the Department of Computer and Information Science in the Engineering School. He is also a member of the Institute for Biomedical Informatics (IBI). In 2018 Dr. Barash was tenured and became an Associate Professor. His lab was the first to offer tools for mapping, quantifying, and visualizing complex splicing variations, showing these comprise over 30% of the human transcriptome variations (Vaquero et al, Elife 2016). The tools the BioCiphers lab develops to quantify and predict aberrant splicing have been instrumental in studying RNA splicing defects in cancer, immunotherapy, and other disease (e.g. Sotillo et al Cancer Discovery 2015, Rivera et al PNAS 2021) and have been licensed by startup companies as well as large companies such as Pfizer, GSK ,and BioGen. Since 2020 Dr. Barash has been advising several companies in the RNA therapeutics space and helped found Ladder TX as its Chief of AI, leading AI R&D.

My full CV

Scientific Focus

I am interested in solving problems from the bio-medical field using machine learning and probabilistic graphical models in particular.

Why machine learning and computational biology?
Current high-throughput experimental technologies make bio-medical research incredibly rich with computational challenges tangled with fundamental scientific questions. To answer these questions we need a good handle on both the bio-medical and computational aspects. Specifically, these high-throughput experiments produce large and noisy datasets with complex relations, making machine learning a particularly useful approach for analyzing these data. I develop probabilistic models that integrate diverse sources of genomic and genetic data to decipher cell regulatory mechanisms. I then use these models to produce testable hypotheses about novel regulatory mechanisms, and how these mechanisms go awry in human disease.

What about wet lab?
The web lab component of the lab serves to validate hypotheses generated by our models, and provide feedback for further model improvements. With our collaborators we also work to design the experimental data that serves as input for our algorithms. In recent years we expanded to develop, together with our collaborators, new high-throughput assays for measuring different aspects of RNA processing and then feed those measurements into our computational models for quantification and inference.

What specific areas do you focus on?
We focus on understanding RNA biogensis, its regulation, and its role in human disease and in phenotipic diversity. Much of our work involves modeling alternative splicing regulation and non-coding regulatory elements in the 5’/3′ UTR. The lab works in three main directions that pose computational, engineering, and experimental challenges:

• Deriving new mechanistic insights into RNA biogenesis.
• Applying our predictive algorithms for RNA processing to the study of human disease and phenotipic diversity.
• Developing software tools that allow the greater scientific community to employ our algorithms.

Topics

• ​Machine learning
• Computational Biology
• Bioinformatics
• RNA biogenesis
• Alternative splicing
• Genetic variations and genomics of human disease

Teaching

• GCB 537 – Advanced Computational Biology (part of GCB graduate program, co-directed with Prof. Li-San Wang).
• CIS 700-001  (tentative) – Advanced Machine Learning in Computational Biology.
• CIS 700-001 (summer & fall 2016) Deep Learning intro and beyond (covering deeplearningbook.org cover to cover + related current papers)
• CIS 800-001 (spring 2018) “Peeking into the black box of (deep) learning models” – current research on model interpretation.
• CIS 800-002 (fall 2021) “Advanced topics in deep learning for CompBio”
• GCB/CAMB 752 – I moderate the sessions about transcriptome methods & analysis in Prof. Diskin’s Genomics seminar.

Scientific Groups

• RNA Processing

Sara Cherry, Ph.D.

Therapeutics Group Lead
Lab Website

Contact Information

University of Pennsylvania
3450 Hamilton Walk
Philadelphia, PA 19104

Publications

Search PubMed For Articles

Links

Search PubMed For Articles
Cherry Lab Website

Education

B.S. (Chemistry) U.C. Berkeley, 1994. Ph.D. (Biology) MIT, 2000.

Description of Research Expertise

Research Interests
Genetic and mechanistic studies of viral-host interactions

Key words:
emerging virus, coronavirus, arbovirus, genomics, antivirals, genetics, Drosophila, innate, immunity

Description of Research
The Cherry Lab is interested in genetic and mechanistic studies of viral-host interactions. The Lab uses chemical and genetic screening technologies to explore the interface between viruses and hosts. The laboratory performs a wide array of cell-based screens in human and insect cells studying emerging viruses with a historical focus on arthropod-borne viruses such as chikungunya and zika virus. Innate immunity is the first line of defense against viruses and much of the recognition of these invaders is at the level of nucleic acid recognition. Arthropod-borne human viruses are RNA viruses and we are examining the role of RNA binding proteins and the RNA decay machinery in innate antiviral defense against these viruses in human cells. Since these viruses can infect diverse tissues we are also exploring antiviral innate signaling activities in distinct cell types including neurons, endothelial cells, and myeloid lineages. We have demonstrated cell-type specific immune pathways. Moreover, as these arthropod-borne viruses infect the vector insect enterically, we use Drosophila to model these intestinal infections to explore the role of the microbiota and innate defenses in the gut in the response to enteric arboviral infections. Projects include understanding how dysbiosis impacts susceptibility and discovering the bacterial products that impact infection. The recent coronavirus pandemic has led us to use our screening technologies to identify drugs that have antiviral activity as well as the role of innate pathways in controlling infection of SARS-CoV-2 in respiratory cells. The laboratory has many projects exploring diverse areas of viral-host interactions and innate immunity.
In addition, the Cherry lab has extended their studies to precision medicine and oncology. In collaborations across UPENN including the high-throughput screening core, oncologists, and pathologists the lab has developed a pipeline to test patient tumor cells for sensitivities to chemotherapeutics in an effort to personalize treatments. Work in acute myelogenous leukemia has demonstrated clear differences in patient responses and has uncovered new dependencies that will be translated into new treatment strategies in the future.

Rotation Projects:
Interested students can work on diverse aspects of viral-host interactions of emerging viruses from arboviruses to coronaviruses. They can involve the study of factors that facilitate infection such as entry pathways or the study of innate immune mechanisms at play.

Lab personnel:
Megha Basavappa– IGG MD/Ph.D. Student
Jorge Acuña– CAMB Ph.D. Student
Trevor Griesman– CAMB Ph.D. Student
Iulia Tapescu– BMB Ph.D. Student
Matt Tracey– BMB Ph.D. Student
Rachel Braun – BMB Ph.D. Student
Guangda Shi– Postdoctoral Fellow
Jaeseung Lee– Postdoctoral Fellow
Max Ferretti– Postdoctoral Fellow
Minghua Li– Postdoctoral Fellow
Steven Miller– Postdoctoral Fellow
Zienab Etwebi– Postdoctoral Fellow
Beth Gold– Research Technician
Alex Huber– Research Specialist
Jesse Hulahan– Research Specialist
Jesse Miller– Research Specialist
Kasirajan Ayyanathan– Research Specialist

Selected Publications

Sansone, C., Cohen, J., Yasunaga, A., Xu, J., Osborn, G., Subramanian, H., Gold, B., Buchon, N. and Cherry, S.: Microbiota-dependent priming of antiviral intestinal immunity in Drosophila. Cell Host Microbe 18(5): 571-81, Nov 2015 Notes: Spotlight in Trends in Microbiology, News and Views, Nature Microbiology.

Beiting, D.P., Hidano, S. Fang, Q. Baggs, J.E., Geskes, J.M., Wherry, J.E., Hunter, C.A., Roos, D.S., and Cherry, S. : A Genomic Screen Identifies the Orphan Nuclear Receptor TLX as an Enhancer of STAT1-mediated Transcription and Immunity to Toxoplasma gondii. PLOS Biology 13(7): e1002200, 2015 Notes: Synopsis in PLOS Biology.

Hopkins, K.C., Tartell, M.A., Herrmann, C., Hackett, B.A., Taschuk, F., Panda, D., Menghani, S., Sabin, L.R., Cherry, S.: Virus-induced translational arrest through 4EBP1/2-dependent decay of 5’TOP mRNAs restricts viral infection. Proc. Natl. Acad. Sci. USA 112(22): E2920-9, Jun 2015.

Hackett, B.A., Yasunaga, A., Panda, D., Tartell, M., Hopkins, K., Hensley, S.E., and Cherry S: RNASEK is required for internalization of diverse acid-dependent viruses. Proc. Natl. Acad. Sci. USA 112(25): 7797-802, Jun 2015 Notes: Epub 2015 Jun 8.

Moy, R.H, Cole, B.S., Yasunaga, A., Gold, B., Shankarling, G., Varble, A. Molleston, J., tenOever, B.R., Lynch, K.W. and Cherry S. : Stem loop recognition by DDX17 facilitates miRNA processing and antiviral defense. Cell 178(4): 764-77, Aug 2014.

Panda, D., Pascual-Garcia, P., Dunagin, D., Tudor, M., Hopkins, K.C., Xu, J., Gold, B., Raj, A., Capelson, M. and Cherry, S. : Nup98 promotes antiviral gene expression to restrict RNA virus infection in Drosophila. Proc. Natl. Acad. Sci. USA 111(37): E3890-9, 2014.

Scientific Groups

Therapeutics

Affiliated Cores

Kathy Fange Liu, Ph.D.

Nucleoside-modification Group Lead
Kathy Fange Liu, Ph.D.'s Website

Lab Website
Lab Twitter

Contact Information

University of Pennsylvania
415 Curie Boulevard
Philadelphia, PA 19104

Links

Kathy Liu Group Website
Faculty Page
Faculty Page In Institute Of Regenerative Medicine
Faculty Page In Cell And Molecular Biology Graduate Group
Kathy Liu Group Twitter

Description of Research Expertise

I have a broad background in biochemistry (enzymology), biophysics (biophysical spectroscopy and X-ray crystallography), nucleic acid biology, molecular biology, and cell biology. My laboratory is interested in (1) the mechanisms and consequences of the interplay of multiple RNA modifications in mRNA, tRNA, and rRNA, particularly with regards to their impacts on human disease, and (2) how epitranscriptomics contributes to sex-biased human physiological and pathological processes.

In my Ph.D. study, I carried out biochemical and biophysical characterizations of a human nuclear metalloprotein with previously unknown function and identified its roles in gene expression regulation in a redox-dependent manner. Also, my graduate work on the structure-function relationships of enzymes in the tryptophan-kynurenine pathway facilitated the understanding of the mechanistic enzymology of NAD+ biosynthesis. I developed a wide range of expertise in enzymology and biophysics through the studies of mechanistic enzymology, especially in stopped-flow UV-vis, EPR, and Mössbauer spectroscopic characterizations and time-lapse crystallography snapshots of the catalytic cycle intermediates (determined 40 protein structures and deposited in Protein Data Bank). In my postdoctoral training, I become interested in studying the functions of RNA modifying enzymes and RNA binding proteins in neuronal development and energy metabolism regulation. My major contribution during this period was the identification of the first transfer RNA (tRNA) demethylase enzyme (i.e., an eraser of the modification) and elucidation of an unprecedented translational regulation mechanism through enzyme-mediated tRNA demethylation. This finding, together with the previously identified reversible regulation of mRNA modifications, collectively led to the notion that methyltransferase and demethylase enzymes reversible controls the methylation status of multiple RNA species.

I aim to combine my knowledge of enzymology, biochemistry, spectroscopy, structural biology, and RNA biology to address fundamental research questions that how dysregulation of RNA binding proteins and RNA modifying enzymes contribute to neurological disorders. In addition, my lab has a long interest in the sex-specific features in the physiology and pathology in the neuronal system.

Selected Publications

Hui Shen, Amber Yanas, Michael C. Owens, Celia Zhang, Clark Fritsch, Charlotte M. Fare, Katie E. Copley, James Shorter, Yale E. Goldman, and Kathy Fange Liu: Sexually dimorphic RNA helicases DDX3X and DDX3Y differentially regulate RNA metabolism through phase separation. Mol. Cell 82, 1-16, May 2022.

Shen H, Gonskikh Y, Stoute J, Liu KF.: Human DIMT1 generates N26,6A-dimethylation-containing small RNAs. J. Biol. Chem. 297: 101146, Aug 2021.

Owens MC, Zhang C, Liu KF.: Recent technical advances in the study of nucleic acid modifications. Mol. Cell 81: 4116-4136, Aug 2021.

Shen H, Ontiveros RJ, Owens MC, Liu MY, Ghanty U, Kohli RM, Liu KF.: TET-mediated 5-methylcytosine oxidation in tRNA promotes translation. J. Biol. Chem. 296, 2021.

Stoute J, Liu KF.: CLIP-Seq to identify targets and interactions of RNA binding proteins and RNA modifying enzymes. Methods Enzymol. 658: 419-434, 2021.

Wang, Yifan, Liu, Kathy Fange, Yang, Yu, Davis, Ian, Liu, Aimin: Observing 3-hydroxyanthranilate-3,4-dioxygenase in action through a crystalline lens. Proc. Natl. Acad. Sci. U. S. A. 117: 19720-19730, Aug 2020.

Shen, H., Stoute, J., Liu, K. F.: Structural and catalytic roles of the human 18S rRNA methyltransferases DIMT1 in ribosome assembly and translation. J. Biol. Chem. 295(34): 12058-12070, Aug 2020.

Ontiveros, R. Jordan, Shen, Hui, Stoute, Julian, Yanas, Amber, Cui, Yixiao, Zhang, Yuyu, Liu, Kathy Fange: Coordination of mRNA and tRNA methylations by TRMT10A. Proc. Natl. Acad. Sci. U. S. A. 117: 7782-7791, Feb 2020.

Ontiveros, R. Jordan, Stoute, Julian, Liu, Kathy Fange: The chemical diversity of RNA modifications. Biochem. J. 476(8): 1227-1245, Apr 2019.

Yanas A, Liu KF.: RNA modifications and the link to human disease. Methods Enzymol. 626: 133-146, 2019.

Scientific Groups

• Nucleoside-modification

Ted Krieder, M.D., PH.D.

Assistant Professor, Division of Infectious Diseases, Department of Medicine, University of Pennsylvania

Room 4072, 1 UCity

Areas of Research: Immunogen design, mRNA gene therapy, HIV, Infectious Diseases

Viruses that persist – such as lentiviruses, herpesviruses, and papillomaviruses – are common, pathogenic, and reactivatable even after long periods of dormancy. My group applies the mRNA platform in three domains to study, prevent, treat, and cure persistent pathogens:

1. Immunogen design. Due to inherent variability, conformational flexibility, dense glycosylation, and more, the target of the HIV antibody response, Env, has proven a poor immunogen. We have developed methods to produce genetically diverse, stabilized Env immunogens. Many of these design concepts exploit basic lentiviral virology and are used to interrogate fundamental concepts in vaccine immunology.
2. Passive antibody delivery. mRNA can express any protein, including the heavy and light chains of an antibody. We have developed a platform for the expression of any antibody, bispecific, or otherwise engineered monoclonal from mRNA. We seek to interrogate host-pathogen dynamics using mRNA-encoded antibodies and test whether transient antibody expression can prevent or treat infections for which antibody interventions have not been investigated.
3. T cell gene therapy. Delivery vehicles like lipid nanoparticles can be chemically modified to alter their cellular tropism. We have applied these techniques to retarget mRNA delivery to various T cell subsets. Current efforts apply these strategies to reverse HIV latency and alter T cell immunobiology. These projects, which shed light on fundamental viral pathogenesis and T cell function, are all designed to simultaneously further develop novel interventions that can be translated into human use. 

Kristen W. Lynch, Ph.D.

Basic Science Group Lead
Kristen W. Lynch, Ph.D.'s Website

Benjamin Rush Professor of Biochemistry

Department: Biochemistry and Biophysics

Contact Information

Department of Biochemistry and Biophysics, Stellar-Chance Labs 909B
422 Curie Blvd
Philadelphia, PA 19104-6059
Office: 215-573-7749
Fax: 215-573-8899
Email: klync@pennmedicine.upenn.edu

Publications

Search PubMed For Articles

Links

Search PubMed For Articles
Lynch Lab Website
RNA Group At Penn

Education:

B.A. Harvard University, 1990. Ph.D. Harvard University, 1996.

Description of Research Expertise

RESEARCH INTERESTS: mechanisms of regulation of alternative splicing, antigen-induced splicing in T cells

KEY WORDS: RNA binding proteins, alternative splicing, gene regulation, T cells

DESCRIPTION OF RESEARCH:
Recent insight into the human genome has revealed that most genes encode multiple distinct protein isoforms through the process of alternative pre-mRNA splicing. My laboratory is focused on understanding the biochemical mechanisms and regulatory networks that control alternative splicing in response to antigen-challenge of the human immune system. In addition, we are working to characterize the physiological consequences of this mode of gene regulation. Recently we have identified ~150 genes that exhibit an alteration in isoform expression in response to T cell stimulation. Through our initial work on the regulated splicing of the protein tyrosine phosphatase CD45, we have identified the regulatory sequence and proteins that controls activation-induced isoform expression of CD45 as well as several other genes essential for T cell function. This work is on-going as we seek to understand the mechanism of this regulation in more molecular detail. Moreover the analysis of binding specificity of the proteins involved in signal-responsive regulation is allowing us to predict further examples of regulated splicing in the immune system. Finally, the generation of mice deficient in their expression of critical splicing regulatory proteins is allowing us to dissect the functional significance of alternative splicing for the proper function of the mammalian immune system. Together these studies are providing new insights into the mechanisms and consequences of RNA-based gene regulation in the cellular response to environmental stimuli.

ROTATION PROJECTS:
1. Characterization of sequences that regulate alternative splicing
2. Identification of novel targets of signal-induced splicing in T cells
3. Mutational analysis of proteins that control alternative splicing

Selected Publications

Slaff B, Radens CM, Jewell P, Jha A, Lahens NF, Grant GR, Thomas-Tikhonenko A, Lynch KW, Barash Y.: MOCCASIN: a method for correcting for known and unknown confounders in RNA splicing analysis. Nat Commun 12: 3353, Jun 2021.

Rivera OD, Mallory MJ, Quesnel-Vallières M, Chatrikhi R, Schultz DC, Carroll M, Barash Y, Cherry S, Lynch KW.: Alternative splicing redefines landscape of commonly mutated genes in acute myeloid leukemia. Proc Natl Acad Sci U S A 118: e2014967118, Apr 2021.

Thompson MG, Dittmar M, Mallory MJ, Bhat P, Ferretti MB, Fontoura BM, Cherry S, Lynch KW.: Viral-induced alternative splicing of host genes promotes influenza replication. Elife 9: e55500, Dec 2020.

Radens CM, Blake D, Jewell P, Barash Y, Lynch KW.: Meta-analysis of transcriptomic variation in T-cell populations reveals both variable and consistent signatures of gene expression and splicing. RNA 26: 1320-1333, October 2020.

Mallory MJ, McClory SP, Chatrikhi R, Gazzara MR, Ontiveros RJ, Lynch KW.: Reciprocal regulation of hnRNP C and CELF2 through translation and transcription tunes splicing activity in T cells. Nucleic Acids Res 48: 5710-5719, Jun 2020.

Agosto LM, Gazzara MR, Radens CM, Sidoli S, Baeza J, Garcia BA, Lynch KW.: Deep profiling and custom databases improve detection of proteoforms generated by alternative splicing. Genome Res 29: 2046-2055, December 2019.

Chatrikhi R, Mallory MJ, Gazzara MR, Agosto LM, Zhu WS, Litterman AJ, Ansel KM, Lynch KW: RNA binding protein CEFL2 regulates signal-induced alternative polyadenylation by competing with enhancers of the polyadenylation machinery. Cell Reports 28: 2795-2806, September 2019.

Black KL, Naqvi AS, Asnani M, Hayer KE, Yang SY, Gillespie E, Bagashev A, Pillai V, Tasian SK, Gazzara MR, Carroll M, Taylor D, Lynch KW, Barash Y, Thomas-Tikhonenko A.: Aberrant splicing in B-cell acute lymphoblastic leukemia. Nucleic Acids Research 47(2): 1043, January 2019.

Zhang K, Shang G, Padavannil A, Wang J, Sakthivel R, Chen X, Kim M, Thompson MG, García-Sastre A, Lynch KW, Chen ZJ, Chook YM, Fontoura BMA: Structural-functional interactions of NS1-BP protein with the splicing and mRNA export machineries for viral and host gene expression. Proceedings of the National Academy of Sciences of the US 115(52): E12218-E12227, December 2018.

McClory SP, Lynch KW, Ling JP : HnRNP L represses cryptic exons. RNA 24(6): 761-768, June 2018.

Scientific Groups

• Basic Science

Michael J. Mitchell, Ph.D.

Lipid nanoparticles (LNP) and other delivery systems Group Lead and LNP Core Lead
Michael J. Mitchell, Ph.D.'s Website

Contact Information

University of Pennsylvania
School of Engineering and Applied Science
240 Skirkanich Hall, 210 S. 33rd Street
Philadelphia, PA 19104

Honors and Awards

 NIH Director’s New Innovator Award – 2018, Burroughs Wellcome Fund Career Award at the Scientific Interface – 2018, STAT News Wunderkind Award – 2017, Merck Research Advances in Delivery Science Award, Controlled Release Society – 2017, American Association for Cancer Research (AACR) Scholar in Cancer Research – 2016, Young Investigator Council, Tissue Engineering Parts A, B, C – 2016

Research Expertise: 

Bioengineered Therapeutics | Devices and Drug Delivery | Biomaterials | Cellular Engineering | Molecular Engineering | Tissue Engineering | Cell Mechanics | Systems and Synthetic Bioengineering | Nanotechnology | Immunoengineering | Immunotherapy | Genome Editing | Immunoengineering | Immunotherapy

The Mitchell Lab is based in the Department of Bioengineering at the University of Pennsylvania. Our research lies at the interface of biomaterials science, drug delivery, and cellular and molecular bioengineering to fundamentally understand and therapeutically target biological barriers. We apply our research findings and the technologies developed to a range of human health applications, including cancer metastasis, immunotherapy, genome editing, cardiovascular disease, and regenerative medicine. Current research projects include: synthesis of novel biomaterials and nanoparticles for the delivery of nucleic acids (siRNA, miRNA, mRNA, CRISPR-Cas9) for cancer therapy; engineering of immune cells for immunotherapy and vaccines; investigating the influence of biomaterial chemical structure on in vivo transport to target cells and tissues using high-throughput screening platforms; and novel drug delivery technologies for tissue engineering and regenerative medicine. Mike has received an NIH National Research Service Award, the NIH Director’s New Innovator Award, and a Career Award at the Scientific Interface from the Burroughs Wellcome Fund, recognizing interdisciplinary researchers who are “bridging science fiction with reality.”

Education:

NIH Postdoctoral Fellow Chemical Engineering 2017 – Massachusetts Institute of Technology
PhD Biomedical Engineering 2014 – Cornell University
MS Biomedical Engineering 2012 – Cornell University
BE/ME Biomedical Engineering and Materials Science 2009 – Stevens Institute of Technology

Scientific Groups

• Lipid nanoparticles (LNP) and other delivery systems
• LNP Core

Vladimir Muzykantov, M.D., PH.D

LNP Therapeutic Targeting Group Lead and Co-Director of Targeting Core

Contact Information

University of Pennsylvania
Perelman School of Medicine
10-105 Smilow Center for Translational Research
3400 Civic Center Blvd
Philadelphia, PA 19104

Department Website

Publications

Search PubMed for articles

Links

Search PubMed for articles
Primary Work Website
Pharmacological Sciences Graduate Group Faculty

Description of Research Expertise

Research Interests:
Drug/gene targeting and vascular biology

Particular areas of interest/expertise include the recognition of surface antigens on normal or pathologically altered endothelial cells; vascular inflammation and leukocytes adhesion; mechanisms of oxidative stress and antioxidant protection of the endothelium; evaluation of specific markers of endothelial injury; immunotargeting of antioxidant enzymes, fibrinolytics and genes to the pulmonary endothelium; pulmonary pathophysiology; lung ischemia/reperfusion; prolongation of enzymes life-time in the bloodstream; controlled elimination of radiolabeled antibodies or pathogens from the bloodstream; exploration of red blood cells as carriers for prolonged circulation and site-specific delivery of drugs (fibrinolytics and anticoagulants); regulation of fibrinolysis and complement; mechanisms and regulation of intracellular targeting/trafficking of drugs.

Research Summary
The laboratory is focused on several projects. First is the targeting of drugs (enzymes either degrading or generating oxidants, fibrinolytics, interferon, antisense oligos and genes) to the pulmonary vascular endothelium. The purpose is to develop strategies for controlled site-specific delivery of a drug to the defined subcellular compartments of the pulmonary endothelium. For example, genetic material must be delivered into the nucleus, antioxidants must accumulate in the cytoplasm, and fibrinolytics must avoid internalization. We therefore study how carrier antibodies and their derivatives recognize endothelium, and characterize cellular trafficking and local effects of the targeted agents in cell cultures, perfused animal lungs and in intact animals. Our research includes identification of the molecules localized on the surface of endothelium useful as targets for drug delivery to either normal or pathologically challenged endothelium. Endothelium-specific antigens may serve as such targets. Affinity carriers that are currently explored in our laboratory include monoclonal antibodies (and their fragments) to: angiotensin-converting enzyme (ACE), thrombomodulin and surface adhesion molecules, ICAM, PECAM, P- and E-selectins. We have characterized carriers and their modifications providing: i) a drug with an affinity to endothelium (recognition and targeting) and, ii) drug delivery in a proper cellular compartment (sub-cellular addressing). Targeting to either surface (by non-internalizable carriers) or intracellularly has been documented in cell culture, perfused lungs and in rodents in vivo.

Secondly, we explore red blood cells (RBC) as natural carriers for drugs. We have developed an original methodology for effective conjugation of large amounts of a drug (e.g., fibrinoytic enzymes or receptors for plasminogen activators) on RBC, without loss of biocompatibility of the complex. Conjugation provides prolongation of half-life of plasminogen activators in vivo by orders of magnitude and offers specific transfer of the conjugated protein (tPA, uPA-receptor) to the pulmonary endothelium. Both mechanism of the transfer (tentatively via exchange of GPI-anchored membrane proteins between RBC and endothelium) and potential therapeutic applications of RBC-conjugated fibrinolytics (treatment/prevention of pulmonary embolism/deep vein thrombosis) are in the focus of the research. We also explore RBC as carriers for intracellular drug delivery in phagocyte cells in the reticuloendothelial tissue (liver and spleen) and endothelial cells.

Selected Publications

Glassman PM, Villa CH, Marcos-Contreras OA, Hood ED, Walsh LR, Greineder CF, Myerson JW, Shuvaeva T, Puentes L, Brenner JS, Siegel DL, Muzykantov VR.: Targeted In Vivo Loading of Red Blood Cells Markedly Prolongs Nanocarrier Circulation. Bioconjug Chem. June 2022.

Parhiz H, Brenner JS, Patel PN, Papp TE, Shahnawaz H, Li Q, Shi R, Zamora ME, Yadegari A, Marcos-Contreras OA, Natesan A, Pardi N, Shuvaev VV, Kiseleva R, Myerson JW, Uhler T, Riley RS, Han X, Mitchell MJ, Lam K, Heyes J, Weissman D, Muzykantov VR.: Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation (IE). J Control Release(344), 50-61, Apr 2022.

Ferguson LT, Hood ED, Shuvaeva T, Shuvaev VV, Basil MC, Wang Z, Nong J, Ma X, Wu J, Myerson JW, Marcos-Contreras OA, Katzen J, Carl JM, Morrisey EE, Cantu E, Villa CH, Mitragotri S, Muzykantov VR, Brenner JS.: Dual Affinity to RBCs and Target Cells (DART) Enhances Both Organ- and Cell Type-Targeting of Intravascular Nanocarriers. ACS Nano.(16), 4666-4683, Mar 2022.

Wang Z, Hood ED, Nong J, Ding J, Marcos-Contreras OA, Glassman PM, Rubey KM, Zaleski M, Espy CL, Gullipali D, Miwa T, Muzykantov VR, Song WC, Myerson JW, Brenner JS. : Combating complement’s deleterious effects on nanomedicine by conjugating complement regulatory proteins to nanoparticles. Adv Mater. Feb 2022.

Myerson JW, Patel PN, Rubey KM, Zamora ME, Zaleski MH, Habibi N, Walsh LR, Lee YW, Luther DC, Ferguson LT, Marcos-Contreras OA, Glassman PM, Mazaleuskaya LL, Johnston I, Hood ED, Shuvaeva T, Wu J, Zhang HY, Gregory JV, Kiseleva RY, Nong J, Grosser T, Greineder CF, Mitragotri S, Worthen GS, Rotello VM, Lahann J, Muzykantov VR, Brenner JS. : Supramolecular arrangement of protein in nanoparticle structures predicts nanoparticle tropism for neutrophils in acute lung inflammation. Nanotechnol 17(1): 86-97, Jan 2022.

Parhiz H, Brenner JS, Patel P, Papp TE, Shahnawaz H, Li Q, Shi R, Zamora M, Yadegari A, Marcos-Contreras OA, Natesan A, Pardi N, Shuvaev VV, Kiseleva R, Myerson J, Uhler T, Riley RS, Han X, Mitchell MJ, Lam K, Heyes J, Weissman D, Muzykantov V. : Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation(IE). J Control Release Dec 2021.

Tutwiler V, Litvinov RI, Protopopova A, Nagaswami C, Villa C, Woods E, Abdulmalik O, Siegel DL, Russell JE, Muzykantov VR, Lam WA, Myers DR, Weisel JW. : Pathologically stiff erythrocytes impede contraction of blood clots: Reply to comment. J Thromb Haemost. 19(11): 2894-2895, Nov 2021.

Nikfar M, Razizadeh M, Paul R, Muzykantov V, Liu Y.: A numerical study on drug delivery via multiscale synergy of cellular hitchhiking onto red blood cells. Nanoscale Sep 2021 Notes: doi: 10.1039/d1nr04057j. Epub ahead of print.

Tutwiler V, Litvinov RI, Protopopova A, Nagaswami C, Villa C, Woods E, Abdulmalik O, Siegel DL, Russell JE, Muzykantov VR, Lam WA, Myers DR, Weisel JW.: Pathologically stiff erythrocytes impede contraction of blood clots. J Thromb Haemost. July 2021 Notes: doi: 10.1111/jth.15407. Epub ahead of print.

Tombácz I, Laczkó D, Shahnawaz H, Muramatsu H, Natesan A, Yadegari A, Papp TE, Alameh MG, Shuvaev V, Mui BL, Tam YK, Muzykantov V, Pardi N, Weissman D, Parhiz H: Highly efficient CD4+ T cell targeting and genetic recombination using engineered CD4+ cell-homing mRNA-LNP. Mol Ther. Jun 2021.

Scientific Groups

• LNP Therapeutic Targeting
• Targeting Core

Hamideh Parhiz, Ph.D.

Co-Director of Targeting Core

1256 KRB II/III

421 Curie Blvd

Philadelphia, PA 19104

The Parhiz Lab is located in the Department of Systems Pharmacology and Translational Therapeutics at Penn Medicine, University of Pennsylvania. Our lab develops novel nucleic acid delivery systems, including a new generation of targeted lipid nanoparticle (tLNP), for in vivo cellular reprogramming. We leverage these systems for mRNA-based therapeutics in a variety of non-vaccine applications such as inherited diseases, acquired or congenital hematopoietic conditions, cancers, fibrosis, and acute inflammatory conditions. We also investigate the mechanisms underlying the enhancement of delivery systems such as the ones related to more favorable pharmacokinetic profile, to apply those principles in designing more effective gene and mRNA therapeutics.  Currently, the targeted LNP-mRNA platform we design serves as the foundation for ongoing academic programs and industrial product developments.

Stefano Rivella, Ph.D.

Leader of the RNA Gene Therapeutics Group
Stefano Rivella, Ph.D.'s Website

Stefano Rivella, PhD, the Kwame Ohene-Frempong endowed chair in Pediatric Hematology and scientific director of the Comprehensive Center for the Cure of Sickle Cell Disease and Other Red Blood Cell Disorders at Children’s Hospital of Philadelphia, is an expert in the use of lentiviral vectors for modulation of gene expression and gene transfer into hematopoietic stem cells and for the cure of hematological disorders. More recently, he expanded his focus on developing tools for RNA delivery (gene editing and RNA therapies) to treat hematological and metabolic disorders.

His research program generated the first adult mouse models of a- and b-thalassemia major and contributed to the creation of the first lentiviral vectors that corrected the hemoglobin synthesis in mice affected by b-thalassemia. This led the way to gene therapy clinical trials for b-thalassemia and sickle cell disease. An advanced vector generated in Dr. Rivella’s Lab for the cure of both b-thalassemia and sickle cell disease has been recently approved by the U.S. Food and Drug Administration for a clinical trial that will start at CHOP.

The Rivella Lab also is studying the role of seminal factors contributing to pathophysiology of hematopoiesis-, inflammation-, and iron-related disorders, such as dyserythropoietic anemias, polycythemia vera, anemia of inflammation, and hemochromatosis, to name a few. Based on some of these studies, the lab is developing or contributing to the characterization of novel therapeutics, while several pharmaceutical companies are currently testing new drugs based on his discoveries.

Bin Tian, Ph.D.

RNA Binding Proteins Group Lead
btian @ wistar.org

Contact Information

Gene Expression and Regulation Program

Ellen and Ronald Caplan Cancer Center

The Wistar Institute

3601 Spruce Street

Philadelphia, PA 19104

Description of Research Expertise

Much of the regulation of a protein-coding gene, during the flow of genetic information from DNA to protein, is executed at the RNA stage. The mRNA life includes several key events, such as pre-mRNA processing, nuclear export, mRNA decay, translation, and subcellular localization. Over 1,000 RNA-binding proteins (RBPs) have been identified in the human genome. They play critical roles in mRNA biogenesis and metabolism. Which sequences or structures an RBP binds, how does one RBP cooperate with other RBPs in binding to the same mRNA substrate, and what functional consequences a particular RNA-RBP interaction confers to mRNA biogenesis and metabolism are some of the questions we are addressing in the lab. We use interdisciplinary approaches to in our studies, involving techniques in molecular biology, functional genomics, and computational biology.

A major part of our research involves regulation of 3’ end processing of pre-mRNA, also known as cleavage and polyadenylation (CPA). Almost all eukaryotic mRNAs require CPA for 3’ end maturation and proper transcriptional termination. The CPA site, also known as polyA site (PAS), is defined by surrounding sequence motifs that are recognized by the CPA machinery, a mega Dalton protein complex containing over 20 core proteins. Many of the CPA factors are RBPs that interact with specific RNA motifs around the PAS. Additional nuclear RBPs binding near the PAS can substantially influence how a PAS is used. About 70-80% of human protein-coding genes harbor multiple PASs, resulting in expression of alternative polyadenylation (APA) isoforms.

Most APA sites change the length of 3’ untranslated region (3’UTR) of mRNA, leading to 3’UTR APA isoforms. While a distal PAS is typically stronger than a proximal PAS, both have similar conservation levels across mammals; and ~50% of human genes have conserved 3’UTR APA sites, supporting the importance of 3’UTR APA. The median size of an alternative 3’UTR, or aUTR, is about three times longer than that of the constant part of 3’UTR, presenting substantial greater opportunities for RBP interactions. On the other hand, by comparing 3’UTR isoforms, one can reveal 3’UTR-mediated regulatory mechanisms without the influence of other parts of mRNA, such as 5’UTR and coding sequence. We are particularly interested in RBP binding differences between 3’UTR isoforms and how they impact 3’UTR isoform stability, translation, and localization in distinct cellular contexts due to metabolic reprogramming and cellular stress.

A sizeable fraction of human genes also harbor PASs in regions before the last exon, mostly in introns, leading to early termination of transcription. These events, named intronic polyadenylation (IPA), are under the combinatory control of splicing and CPA. As such, the RBPs that regulate either one of the two co-transcriptional processes could substantially impact IPA. While IPA sites in general are less conserved than last exon PASs, ~20% of human genes contain conserved IPA sites. Some IPA events lead to transcripts encoding distinct protein isoforms, as exemplified by the transcript variants encoding membrane or soluble protein isoforms of IgM heavy chain protein reported in early studies. IPA transcripts in general, however, appear unstable as shown in our recent analysis. As such, IPA regulation is an effective mechanism to control gene expression, especially for long genes, which tend to harbor IPA sites. We are examining IPA regulation and functions in cell differentiation, stress response, and cancers.

Links

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https://www.ncbi.nlm.nih.gov/sites/myncbi/bin.tian.1/bibliography/41141877/public/?sort=date&direction=descending

Faculty Page

https://wistar.org/our-scientists/bin-tian

Selected Publications

1. Guvenek A*, Shin J*, De Filippis L, Zheng D, Wang W, Pang ZP, Tian B. (2022). Neuronal cells display distinct stability controls of alternative polyadenylation isoforms, long non-coding RNAs and mitochondrial RNAs. Frontiers in Genetics. 13:840369. *co-first author.
2. Cheng LC*, Zheng D*, Zhang Q, Guvenek A, Cheng H, Tian B. (2021). Alternative 3’UTRs play a widespread role in translation-independent mRNA association with endoplasmic reticulum. Cell Rep. 36:109407. *co-first author.
3. Cheng LC, Zheng D, Baljinnyam E, Sun F, Ogami K, Yeung PL, Hoque M, Shin J, Ding Q, Lu CW, Manley JL, Tian B. (2020). Widespread transcript shortening in through alternative polyadenylation in secretory cell differentiation. Nat Commun. 11:3182.
4. Zheng D*, Cho H*, Wang W*, Rambout X, Tian B^#, Maquat LE^#. (2020). 3’READS+RIP defines differential Staufen1 binding to alternative 3’UTR isoforms and reveals structures and sequence motifs influencing binding and polysome association. 26:1621-1636. *co-first author; #co-corresponding author.
5. Wang R, Zheng D, Wei L, Ding Q, Tian B. (2019) Regulation of intronic polyadenylation by PCF11 impacts mRNA expression of long genes. Cell Rep, 26(10):2766-2778.e6.
6. Chen S*, Wang R*, Zheng D*, Dai H*, Chang X, Wang K, Li W, Fan J, Tian B^#, Cheng H^#. (2019) The mRNA export receptor NXF1 coordinates transcriptional dynamics, alternative polyadenylation and mRNA export. Mol Cell, 74:118-131. *co-first author; #co-corresponding author.
7. Guvenek A, Tian B. (2018). Analysis of alternative cleavage and polyadenylation in mature and differentiating neurons using RNA-seq data. Quant Biol. 6:253-266.
8. Wang R, Zheng D, Yehia G, Tian B. (2018). A compendium of conserved cleavage and polyadenylation events in mammals. Genome Res. 28:1427-1441.
9. Zheng D, Wang R, Ding Q, Wang T, Xie B, Wei L, Zhong Z, Tian B. (2018). Cellular stress alters 3’UTR landscape through alternative polyadenylation and isoform-specific degradation. Nat Commun. 9:2268.
10. Wang R, Nambiar R, Zheng D, Tian B. (2018). PolyA_DB 3 catalogs cleavage and polyadenylation sites identified by deep sequencing in multiple genomes. Nucleic Acids Res. 46(D1):D315-D319.

Blanton Tolbert, Ph.D.

Jacob Gershon Cohen Professor of Biochemistry and Biophysics, RNA Structural Biology Lead

Tolbert is a Professor of Biochemistry and Biophysics at University of Pennsylvania. The research in the Tolbert group focuses on the biochemical mechanisms by which RNA viruses replicate within the cellular environment. His group leverages their fundamental understanding of the molecular biology of these viruses to identify novel targets for therapeutic intervention. The team has collaborated with colleagues to develop compounds with the potential to delay or halt the replication of SARS-CoV-2 and EV-A71.

Tolbert earned a BS in chemistry at University of South Carolina and a PhD in biophysics and structural biology at University of Rochester. He was an HHMI postdoctoral fellow at University of Maryland, Baltimore County, with HHMI Investigator Michael Summers. In 2016, Tolbert received the inaugural Morton L. Mandel Award for Excellence in Research and Service from the CWRU chemistry department. In 2023, he was recognized by the International Society for Antiviral Research with the Diversity in Science and Excellence Award.