This proposal describes a five year career development plan focused on providing the principle investigator (PI) a strong foundation on which to build a successful academic research program. The long-term goal of the PI is to lead a strong NIH funded research program. In the short term this proposal will allow the PI to develop independent lines of research that are both scientifically important and generate a clear change in direction from his current mentor. Work funded by this award will take place at the University of Minnesota in the laboratory of Dr. Joseph Metzger. Dr. Metzger is a noted authority on the utilization of gene transfer technologies to understand cardiac physiology and disease. He is the chair of the department of Integrative Biology and Physiology and has a long track record of successful post-doctoral fellows and graduate students, many of which have gone on to successful careers in academia. In addition to the skills and mentoring of Dr. Metzger, the PI has cultivated a strong network of collaborators and advisors to provide scientific and career advice. The research will focus on the control of coronary artery blood flow in dystrophic cardiomyopathy. Both clinical studies and animal models of muscular dystrophy provide evidence that the regulation of coronary flow is abnormal in muscular dystrophies. The experiments proposed here focus on models of Duchenne muscular dystrophy and limb girdle muscular dystrophy (2C and 2F).
The specific aims are: 1) To evaluate the role of dystrophin and sarcoglycan complex in the modulation of coronary flow in response to changes in endothelial shear stress and hormonal mediated vasoconstriction and vasodilation. 2) To determine the mechanistic link between neuronal nitric oxide synthase (nNOS) and dystrophin in the auto-regulatory control of blood flow in the heart. This work will represent the first detailed examination of coronary blood flow regulation in dystrophic cardiomyopathy. The University of Minnesota provides an excellent environment for basic cardiovascular research. The Lillihei Heart Institute provides excellent core resources and a strong collaborative environment. In short, this environment provides all of the resources required for the PI to develop strong independent lines of investigation.
This project focuses on abnormal regulation of coronary perfusion as a potentially novel pathogenic mechanism underlying the heart disease associated with muscular dystrophy. Duchenne muscular dystrophy is the most common fatal genetic disease and heart failure is an emerging threat to these patients. This project will provide insights into the role of coronary blood flow regulation in the pathophysiology of this disease. Such an understanding could lead to novel therapeutic approaches to redress this progressive and fatal disease.
|Stelter, Zachary; Strakova, Jana; Yellamilli, Amritha et al. (2016) Hypoxia-induced cardiac injury in dystrophic mice. Am J Physiol Heart Circ Physiol 310:H938-48|
|Meyers, Tatyana A; Townsend, DeWayne (2015) Early right ventricular fibrosis and reduction in biventricular cardiac reserve in the dystrophin-deficient mdx heart. Am J Physiol Heart Circ Physiol 308:H303-15|
|Strakova, Jana; Dean, Jon D; Sharpe, Katharine M et al. (2014) Dystrobrevin increases dystrophin's binding to the dystrophin-glycoprotein complex and provides protection during cardiac stress. J Mol Cell Cardiol 76:106-15|
|Townsend, Dewayne (2014) Finding the sweet spot: assembly and glycosylation of the dystrophin-associated glycoprotein complex. Anat Rec (Hoboken) 297:1694-705|
|Sharpe, Katharine M; Premsukh, Monica D; Townsend, DeWayne (2013) Alterations of dystrophin-associated glycoproteins in the heart lacking dystrophin or dystrophin and utrophin. J Muscle Res Cell Motil 34:395-405|
|Townsend, DeWayne; Yasuda, Soichiro; McNally, Elizabeth et al. (2011) Distinct pathophysiological mechanisms of cardiomyopathy in hearts lacking dystrophin or the sarcoglycan complex. FASEB J 25:3106-14|
|Townsend, DeWayne; Daly, Michael; Chamberlain, Jeffrey S et al. (2011) Age-dependent dystrophin loss and genetic reconstitution establish a molecular link between dystrophin and heart performance during aging. Mol Ther 19:1821-5|
|Townsend, Dewayne; Turner, Immanuel; Yasuda, Soichiro et al. (2010) Chronic administration of membrane sealant prevents severe cardiac injury and ventricular dilatation in dystrophic dogs. J Clin Invest 120:1140-50|
|Adhikari, Neeta; Basi, David L; Townsend, Dewayne et al. (2010) Heparan sulfate Ndst1 regulates vascular smooth muscle cell proliferation, vessel size and vascular remodeling. J Mol Cell Cardiol 49:287-93|