Gerald W. Dorn, II, M.D.
Philip & Sima K Needleman Professor
Molecular Cell Biology Program
Molecular Genetics and Genomics Program
Human and Statistical Genetics Program
Rm 760 McDonell Science
cell death, cell signaling, genetic epidemiology, heart failure
Cellular, Molecular, And Genetic Studies Of Cardiac Hypertrophy And Heart Failure
Our lab studies the heart as a model for understanding molecular mechanisms that drive cell growth, phenotypic reprogramming, and death. Heart muscle cells (cardiomyocytes) stop replicating shortly after birth. Therefore, their proliferative or hypertrophic growth is regulated during different developmental stages by distinct gene programs. Our team examines how altered genetic programming leading to pathological cardiomyocyte growth or programmed cell death contributes to diseases such as cardiac hypertrophy, hypertrophic and dilated cardiomyopathy, and heart failure. Because the processes that orchestrate cardiomyocyte growth, morphogenesis, and programmed death are highly conserved across evolution we employ multiple biological platforms to identify and interrogate critical factors. Typically, we use human genetics/genomics to uncover a candidate factor and then dissect the pathway in cultured cells, genetically engineered fruit flies, and/or mice. By creating animal disease models that recapitulate the human condition, and by integrating genomics, proteomics, and bioinformatics with physiological analyses at the organelle, cell, organ, and intact animal level, we derive mechanistic insights that drive novel clinical diagnostics and candidate therapeutics. Our long-term goal is to understand the complex interactions that modulate genetic and epigenetic reprogramming in the heart, and to apply this information to novel small molecular or genetic therapeutics for heritable and acquired human cardiac disease.
Ours is a scientifically and culturally diverse program comprised of talented students, postdoctoral fellows, and research associates. We emphasize scientific creativity and multidisciplinary collaborations within and between different laboratories. Students and postdoctoral fellows typically first engage in an ongoing study and use this as a platform to develop their own independent project, providing a strong foundation for scientific success.
Current research projects include:
Molecular pathways of apoptotic and non-apoptotic cell death.
The balance between cell growth and death determines organ morphogenesis and tissue homeostasis. We identified death genes that are induced in adult hearts by cardiac stress, provoking the non-recoverable cardiomyocyte loss that leads to heart failure. These factors and their interconnected signaling pathways are being investigated in cultured cells, Drosophila, and genetically engineered or surgically manipulated mouse models (13, 19, 21, 22, 24).
microRNA regulation of cardiac gene expression.
microRNAs are regulated in heart disease and modify levels of cardiac mRNAs, thus controlling cardiomyocyte growth, metabolism, contractility, and programmed death. This biological complexity is being studied using a systems biology approach that integrates deep RNA and microRNA sequencing and computational analyses in relevant mouse models of heart stress (1, 4, 6, 16, 18).
Mitochondrial dynamism and cell fate.
We are using a variety of approaches in cells, fruit flies, mice, and humans to uncover the consequences of disturbed mitochondrial fusion and fission on heart disease. We are exploring the roles of mitochondrial fusion factors on mitochondrial genomic integrity, metabolic homeostasis, apoptosis and programmed necrosis, and mitochondrial quality control. (2, 5, 9, 10).
G-protein dependent and independent kinase signaling in the heart.
G-protein coupled receptors regulate almost every facet of cardiac development, function, and stress adaptation. We have developed unique cardiac-specific gene deletion mouse models enabling us to separately define the roles of canonical G-protein/PKC signaling and atypical GRK/β-arrestin signaling in embryonic cardiac development and adult heart disease (7, 11, 12, 14, 20).
Genetic modifiers of human cardiomyopathy.
Using high-throughput genomics in our well-characterized human cohorts we have identified a number of different genetic disease risk factors or disease modifiers that are being investigated in mice or fruit flies expressing the relevant human mutation (3, 5, 8, 15, 17, 20, 23).
List of Representative Publications
1. Hu Y, Matkovich SJ, Hecker PA, Zhang Y, Edwards JR, Dorn GW 2nd. Epitranscriptional orchestration of genetic reprogramming is an emergent property of stress-regulated cardiac microRNAs. [published on line ahead of print Nov. 12, 2012]. Proc Natl Acad Sci USA. 2012.
2. Chen Y, Csordas G, Jowdy C, Schneider TG, Csordas N, Wang W, Liu Y, Kohlhaas M, Meiser M, Bergem S, Nerbonne JM, Dorn GW 2nd, Maack C. Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca2+ crosstalk. Circ Res. 2012;111(7):863-75. PMCID: 3444672.
3. Cresci S, Dorn GW 2nd, Jones PG, Beitelshees AL, Li AY, Lenzini PA, Province MA, Spertus JA, Lanfear DE. Adrenergic-pathway gene variants influence beta-blocker-related outcomes after acute coronary syndrome in a race-specific manner. J Am Coll Cardiol. 2012;60(10):898-907.
4. Dorn GW 2nd, Matkovich SJ, Eschenbacher WH, Zhang Y. A Human 3` miR-499 Mutation Alters Cardiac mRNA Targeting and Function. Circ Res. 2012;110(7):958-67. PMCID: 3320730.
5. Eschenbacher WH, Song M, Chen Y, Bhandari P, Zhao P, Jowdy CC, Engelhard JT, Dorn GW 2nd. Two rare human mitofusin 2 mutations alter mitochondrial dynamics and induce retinal and cardiac pathology in Drosophila. PLoS One. 2012;7(9):e44296. PMCID: 3434137.
6. Matkovich SJ, Hu Y, Eschenbacher WH, Dorn LE, Dorn GW 2nd. Direct and indirect involvement of microRNA-499 in clinical and experimental cardiomyopathy. Circ Res. 2012;111(5):521-31. PMCID: 3429338.
7. Arnon TI, Xu Y, Lo C, Pham T, An J, Coughlin S, Dorn GW 2nd, Cyster JG. GRK2-dependent S1PR1 desensitization is required for lymphocytes to overcome their attraction to blood. Science. 2011;333(6051):1898-903. PMCID: 3267326.
8. Cappola TP, Matkovich SJ, Wang W, van Booven D, Li M, Wang X, Qu L, Sweitzer NK, Fang JC, Reilly MP, Hakonarson H, Nerbonne JM, Dorn GW 2nd. Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation. Proc Natl Acad Sci USA. 2011;108(6):2456-61.
9. Chen Y, Liu Y, Dorn GW 2nd. Mitochondrial Fusion is Essential for Organelle Function and Cardiac Homeostasis. Circ Res. 2011;109(12):1327-31. PMCID: 3237902.
10. Dorn GW 2nd, Clark CF, Eschenbacher WH, Kang MY, Engelhard JT, Warner SJ, Matkovich SJ, Jowdy CC. MARF and Opa1 control mitochondrial and cardiac function in Drosophila. Circ Res. 2011;108(1):12-7.
11. Zhang Y, Matkovich SJ, Duan X, Diwan A, Kang MY, Dorn GW 2nd. Receptor-independent protein kinase Cα (PKCα) signaling by calpain-generated free catalytic domains induces HDAC5 nuclear export and regulates cardiac transcription. J Biol Chem. 2011;286(30):26943-51. PMCID: 3143653.
12. Zhang Y, Matkovich SJ, Duan X, Gold JI, Koch WJ, Dorn GW 2nd. Nuclear effects of G-protein receptor kinase 5 on histone deacetylase 5-regulated gene transcription in heart failure. Circ: Heart Failure. 2011;4(5):659-68. PMCID: 3178677.
13. Chen Y, Lewis W, Diwan A, Cheng EH, Matkovich SJ, Dorn GW 2nd. Dual autonomous mitochondrial cell death pathways are activated by Nix/BNip3L and induce cardiomyopathy. Proc Natl Acad Sci USA. 2010;107(20):9035-42.
14. Kang MY, Zhang Y, Matkovich SJ, Diwan A, Chishti AH, Dorn GW 2nd. Receptor-independent cardiac protein kinase Ca activation by calpain-mediated truncation of regulatory domains. Circ Res. 2010;107(7):903-12. PMCID: 2948630.
15. Matkovich SJ, Van Booven DJ, Hindes A, Kang MY, Druley TE, Vallania FL, Mitra RD, Reilly MP, Cappola TP, Dorn GW 2nd. Cardiac signaling genes exhibit unexpected sequence diversity in sporadic cardiomyopathy, revealing HSPB7 polymorphisms associated with disease. J Clin Invest. 2010;120(1):280-9. PMCID: 2798680.
16. Matkovich SJ, Wang W, Tu Y, Eschenbacher WH, Dorn LE, Condorelli G, Diwan A, Nerbonne JM, Dorn GW 2nd. MicroRNA-133a protects against myocardial fibrosis and modulates electrical repolarization without affecting hypertrophy in pressure-overloaded adult hearts. Circ Res. 2010;106(1):166-75. PMCID: 2804031.
17. Cresci S, Kelly RJ, Cappola TP, Diwan A, Dries D, Kardia SL, Dorn GW 2nd. Clinical and genetic modifiers of long-term survival in heart failure. J Am Coll Cardiol. 2009;54(5):432-44. PMCID: 2749467.
18. Matkovich SJ, Van Booven DJ, Youker KA, Torre-Amione G, Diwan A, Eschenbacher WH, Dorn LE, Watson MA, Margulies KB, Dorn GW 2nd. Reciprocal Regulation of Myocardial microRNAs and Messenger RNA in Human Cardiomyopathy and Reversal of the microRNA Signature by Biomechanical Support. Circulation. 2009;119:1263-71.
19. Diwan A, Wansapura J, Syed FM, Matkovich SJ, Lorenz JN, Dorn GW 2nd. Nix-mediated apoptosis links myocardial fibrosis, cardiac remodeling, and hypertrophy decompensation. Circulation. 2008;117(3):396-404.
20. Liggett SB, Cresci S, Kelly RJ, Syed FM, Matkovich SJ, Hahn HS, Diwan A, Martini JS, Sparks L, Parekh RR, Spertus JA, Koch WJ, Kardia SL, Dorn GW 2nd. A GRK5 polymorphism that inhibits b-adrenergic receptor signaling is protective in heart failure. Nat Med. 2008;14(5):510-7. PMCID: 2596476.
21. Diwan A, Koesters AG, Odley AM, Pushkaran S, Baines CP, Spike BT, Daria D, Jegga AG, Geiger H, Aronow BJ, Molkentin JD, Macleod KF, Kalfa TA, Dorn GW 2nd. Unrestrained erythroblast development in Nix-/- mice reveals a mechanism for apoptotic modulation of erythropoiesis. Proc Natl Acad Sci USA. 2007;104(16):6794-9.
22. Diwan A, Krenz M, Syed FM, Wansapura J, Ren X, Koesters AG, Li H, Kirshenbaum LA, Hahn HS, Robbins J, Jones WK, Dorn GW 2nd. Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice. J Clin Invest. 2007;117(10):2825-33.
23. Mialet PJ, Rathz DA, Petrashevskaya NN, Hahn HS, Wagoner LE, Schwartz A, Dorn GW 2nd, Liggett SB. b1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nat Med. 2003;9(10):1300-5.
24. Yussman MG, Toyokawa T, Odley A, Lynch RA, Wu G, Colbert MC, Aronow BJ, Lorenz JN, Dorn GW 2nd. Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy. Nat Med. 2002;8(7):725-30.
Last Updated: 11/20/2012 8:53:30 AM