Jonathan A. Epstein, M.D.
University of Pennsylvania
The Perelman School of Medicine
Department of Medicine
Lab: SCTR 9-187-190
Office: SCTR 9-105
3400 Civic Center Blvd
Philadelphia, PA 19104
1. We have demonstrated that engineered T cells (CART cells) can be used to target activated fibroblasts in the diseased heart with resulting improvement in cardiac function. This work has received significant attention (highlighted in the NEJM, Scientific American, the NYTimes and elsewhere) and has opened the field of CART cells to the possibility of providing new treatments for fibrotic disorders.
Rurik JG, Tombácz I, Yadegari A, Méndez Fernández PO, Shewale SV, Kimura T, Younoss SO, Papp TE, Tam YK, Mui BL, Albelda SM, Pure E, June CH, Aghajanian H, Weissman D, Parhiz H, Epstein JA. CAR T cells produced in vivo to treat cardiac injury. Science. 2022 Jan 7;375(6576):91-96. doi: 10.1126/science.abm0594
Rurik JG, Aghajanian H, Epstein JA. Immune cells and immunotherapy for cardiac injury and repair. Circ. Res. 2021 May 28; 128(11):1766-1779. Review
Epstein JA, Rosenthal N, Feldman AM. Teasing the Immune System to Repair the Heart. N Engl J Med. 2020 Apr 23;382(17):1660-1662. Review
Aghajanian H, Kimura T, Rurik JG, Hancock AS, Leibowitz MS, Li L, Scholler J, Monslow J, Lo A, Han W, Wang T, Bedi K, Morley MP, Linares Saldana RA, Bolar NA, McDaid K, Assenmacher CA, Smith CL, Wirth D, June CH, Margulies KB, Jain R, Puré E, Albelda SM, Epstein JA. Targeting cardiac fibrosis with engineered T cells. Nature. 2019 Sep;573(7774):430-433. PMCID: PMC6752964
2. We have elucidated the role of epigenetics in heart development and we have applied this knowledge to explore novel therapies for adult cardiac disease including ischemia-reperfusion and congestive heart failure. In particular, we demonstrated that histone deacetylase inhibitors can prevent pathologic cardiac hypertrophy, which was counter to the prevailing dogma at the time. More recently, we have shown that nuclear architecture (how chromatin is packaged in three dimensions in the nucleus) contributes to cell identity, gene expression, and developmental competence.
Smith, C.L., Poleshko, A., Epstein, J.A. The nuclear periphery is a scaffold for tissue-specific enhancers. Nucleic Acids Res. 2021; 49: 6181-6195. PMCID: PMC8216274
Poleshko, A., Shah, P.P., Gupta, M., Babu, A., Moreley, M., Manderfield, L.J., Ifkovits, J.L., Dubois, N., Morrisey, E.E., Lazar, M.A., Smith, C.L., Epstein, J.A., Jain, R. Genome–nuclear lamina interactions regulate progenitor cell lineage restriction during cardiogenesis. Cell. 2017 Oct 7. (co-senior author and mentor of first author). PMCID: PMC5683101
Kook H, Lepore JJ, Gitler AD, Lu MM, Wing-Man Yung W, Mackay J, Zhou R, Ferrari V, Gruber P, Epstein JA. Cardiac hypertrophy and histone deacetylase-dependent transcriptional repression mediated by the atypical homeodomain protein Hop. The Journal of Clinical Investigation. 2003;112(6):863-71. PMCID: PMC193673.
Chen F, Kook H, Milewski R, Gitler AD, Lu MM, Li J, Nazarian R, Schnepp R, Jen K, Biben C, Runke G, Mackay JP, Novotny J, Schwartz RJ, Harvey RP, Mullins MC, Epstein JA. Hop is an unusual homeobox gene that modulates cardiac development. Cell. 2002;110(6):713-23.
3. My laboratory has contributed to our understanding of how the neural crest influences cardiac development and to the embryologic and genetic basis of congenital heart disease. Neural crest contribution to the heart was described in the early 1980s by Kirby and colleagues, and our laboratory extended these observations to mammalian systems, performed genetic fate-mapping in mouse models, identified candidate genes for congenital heart defects and described molecular pathways including Notch, Fgf, Wnt and Hippo that regulate cross-talk between neural crest, endothelium and second heart field derivatives in the heart.
Manderfield LJ, Engleka KA, Aghajanian H, Gupta M, Yang S, Li L, Baggs JE, Hogenesch JB, Olson EN, Epstein JA. Pax3 and hippo signaling coordinate melanocyte gene expression in neural crest. Cell Reports. 2014;9(5):1885-95. PMCID: PMC4267159.
Manderfield LJ, High FA, Engleka KA, Liu F, Li L, Rentschler S, Epstein JA. Notch activation of Jagged1 contributes to the assembly of the arterial wall. Circulation. 2012;125(2):314-23. PMCID: PMC3260393.
Katz TC, Singh MK, Degenhardt K, Rivera-Feliciano J, Johnson RL, Epstein JA, Tabin CJ. Distinct compartments of the proepicardial organ give rise to coronary vascular endothelial cells. Developmental Cell. 2012;22(3):639-50. PMCID: PMC3306604.
de la Pompa JL, Epstein JA. Coordinating tissue interactions: Notch signaling in cardiac development and disease. Developmental Cell. 2012;22(2):244-54. PMCID: PMC3285259.
4. We described the molecular basis for cardiovascular manifestations in Type 1 Neurofibromatosis using mouse and zebrafish models, including valvular pulmonic stenosis, endothelial defects and cardiac hypertrophy. We generated a zinc-finger knockout of the Nf1 genes in zebrafish, and demonstrated behavioral defects amenable to small molecule drug screening.
Wolman MA, de Groh ED, McBride SM, Jongens TA, Granato M, Epstein JA. Modulation of cAMP and ras signaling pathways improves distinct behavioral deficits in a zebrafish model of neurofibromatosis type 1. Cell Reports. 2014;8(5):1265-70. PMCID: PMC5850931
Shin J, Padmanabhan A, de Groh ED, Lee JS, Haidar S, Dahlberg S, Guo F, He S, Wolman MA, Granato M, Lawson ND, Wolfe SA, Kim SH, Solnica-Krezel L, Kanki JP, Ligon KL, Epstein JA, Look AT. Zebrafish neurofibromatosis type 1 genes have redundant functions in tumorigenesis and embryonic development. Disease Models & Mechanisms. 2012;5(6):881-94. PMCID: PMC3484870.
Ismat FA, Xu J, Lu MM, Epstein JA. The neurofibromin GAP-related domain rescues endothelial but not neural crest development in Nf1 mice. The Journal of Clinical Investigation. 2006;116(9):2378-84. PMCID: PMC1533876.
Gitler AD, Zhu Y, Ismat FA, Lu MM, Yamauchi Y, Parada LF, Epstein JA. Nf1 has an essential role in endothelial cells. Nature Genetics. 2003;33(1):75-9. PMCID: PMC3079412.
5. We were among the first to show that guidance molecules known to regulate the migration of axons in the central nervous system can also regulate angiogenesis and cardiac development. We have shown that members of the semaphorin and plexin families help to pattern the outflow tract of the heart, the pulmonary veins and coronary arteries, and the peripheral vasculature.
Epstein JA, Aghajanian H, Singh MK. Semaphorin signaling in cardiovascular development. Cell Metabolism. 2015;21(2):163-73. Review
Aghajanian H, Choi C, Ho VC, Gupta M, Singh MK, Epstein JA. Semaphorin 3d and semaphorin 3e direct endothelial motility through distinct molecular signaling pathways. The Journal of Biological Chemistry. 2014;289(26):17971-9. PMCID: PMC4140303.
Degenhardt K, Singh MK, Aghajanian H, Massera D, Wang Q, Li J, Li L, Choi C, Yzaguirre AD, Francey LJ, Gallant E, Krantz ID, Gruber PJ, Epstein JA. Semaphorin 3d signaling defects are associated with anomalous pulmonary venous connections. Nature Medicine. 2013;19(6):760-5. PMCID: PMC3746328.
Gitler AD, Lu MM, Epstein JA. PlexinD1 and semaphorin signaling are required in endothelial cells for cardiovascular development. Developmental Cell. 2004;7(1):107-16.
The Epstein laboratory studies molecular mechanisms of cardiovascular development and stem cell biology, and the implications of these mechanisms for understanding human disease. The lab has a longstanding interest in the genetic causes of congenital heart disease and transcriptional regulation of cell fate determination. Most recently, we have focused on epigenetics, including the role of histone deacetylases in cardiac development and adult heart function. Aims of current projects include gaining an understanding of the three-dimensional packaging of DNA and chromatin in the nucleus (“nuclear architecture”), and the regulation of cell differentiation by protein complexes that tether regions of the genome to the nuclear periphery. The lab has pioneered the concept that interactions between the nuclear lamina and the chromatin contribute to the regulation of entire gene programs that define cardiac cell types.
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