Dorn Lab Research Goals

The goal of Gerald Dorn’s laboratory has been to define stress signaling pathways orchestrating the transition from normal myocardium to failing cardiomyopathy. His publications have been distinguished by scientific rigor, conceptual and technical innovation, and broad investigative impact. Dorn’s work has generated insights into the roles of Gq-proteins, protein kinase C, and β-adrenergic receptor signaling in cardiac hypertrophy, microRNA functioning in heart disease, and genetic polymorphisms as clinical risk modifiers in heart failure. Noteworthy is Dorn’s research dissecting mitochondrial mechanisms of heart disease. Early investigations established that autocrine/paracrine signaling through Gq is sufficient both to induce the genetic program for pathological hypertrophy (Proc Natl Acad Sci USA. 94:8121-8126, 1997, pdf), and to cause heart failure by inducing cardiomyocyte apoptosis (Proc Natl Acad Sci USA. 95:10140-10145, 1998, pdf) (Figure 1).

Figure 1.

Gq mouse hearts showing phenotypes of cardiac hypertrophy and dilated cardiomyopathy.

Gq mouse hearts showing phenotypes of cardiac hypertrophy and dilated cardiomyopathy.

Dorn identified Gq-mediated transcriptional upregulation of the mitochondrial death protein Nix/Bcl-xL as the major factor driving cardiomyocyte apoptosis in hypertrophy (Nat Med. 7:725-730, 2002, pdf, Circulation, 117:396-404, 2008, pdf), and upregulation of related Bnip3 as the cause of apoptotic infarct extension after cardiac ischemia (J Clin Invest. 117:2123-32, 2007, pdf) (Figure 2). He subsequently determined that these Bcl2 factors are re-targeted to cardiac sarcoplasmic reticulum (SR) in heart disease where they control calcium crosstalk between SR and mitochondria that evokes programmed cardiomyocyte necrosis (J Clin Invest. 119:203-212, 2009, pdf, PNAS 107:9035-42, 2010, pdf). Recognizing that mitofusin proteins are integral to this form of inter-organelle communication (Circ Res. 107:903-12, 2010, pdf, Circ Res. 110:265-74, 2012, pdf), Dorn has now uncovered central roles for mitofusins in homeostatic mitochondrial quality control and cardiomyocyte differentiation during embryonic development (Science 340:471-5, 2013, pdf, Science 342:734-7, 2013, pdf). His work has engendered new paradigms relating organelle dynamism to non-canonical mitochondrial functioning in chronic disease.

Figure 2.

Schematic depicting development and progression of cardiomyopathy after ischemic and hypertrophic insults.

Schematic depicting development and progression of cardiomyopathy after ischemic and hypertrophic insults.