WHEN: Thursday, May 8th, 3:00 p.m.
WHERE: HPA I, Room 125

 
Transcription Factors as Therapeutic Targets for Cardiovascular Disease

Evidence is emerging that derangements in cellular energy metabolism and mitochondrial function contribute to common diseases of the heart including hypertensive and diabetic forms of heart failure.  Our group is interested in defining the gene regulatory pathways that control striated muscle fuel utilization and mitochondrial function during normal development and in disease states.  Our work has revealed the importance of the transcriptional coactivator PPARγ coactivator 1a (PGC-1a).  PGC-1a and its relative, PGC-1b, are inducible factors that orchestrate gene regulatory control of metabolic pathways involved in fatty acid and glucose utilization and mitochondrial biogenesis.  The PPAR and ERR family of nuclear receptor transcription factors are key PGC-1a targets. Using gain-of-function transgenic mice and loss-of-function “knock-out” mice, we have learned about the function of the PGC-1 coactivators, ERRs, and PPARs in controlling energy metabolism in the heart, skeletal muscle, and other high energy utilizing tissues.  Interestingly, the PGC-1a cascade is dysregulated in common forms of heart failure.  In hypertensive forms of heart failure, the PGC-1a cascade (PPARa) is deactivated leading to energy “starvation”.  In the diabetic heart, components of the PGC-1 cascade (PPARa) is too active leading to lipid accumulation in myocardium.  Each of these states have been modeled in heart-specific genetically-modified mouse lines.  The murine models will be discussed and implications for new therapeutic approaches in humans will be addressed.

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