Mechanistic Understanding of Hypoxia-Induced Peroxisome loss: Implications for Heart Failure - Project Summary/Abstract
Heart failure is characterized by decreased fatty acid oxidation (FAO) and increased glycolysis.
Increasing FAO is beneficial in animal models of heart failure however why it is beneficial is unclear. FAO
inhibition during heart failure occurs in part due to increased hypoxia during ischemia and ischemic
cardiomyopathy now accounts for nearly 70% of heart failure cases. The mechanisms by which hypoxia inhibits
FAO remain poorly understood. FAO is compartmentalized into mitochondria and peroxisomes. I have
discovered that HIFa, the master regulator in the response to hypoxia, depletes peroxisomes. Mechanistically. I
have identified HIFa activates DEPP1, a protein of unknown function that is necessary and sufficient for hypoxia-
induced peroxisome loss. In Aim 1, I propose complementary biochemical and genetic experiments to identify
the mechanism of DEPP1-mediated peroxisome loss. In Aim 2, I will determine how DEPP1 loss reduces
cardiomyocyte death during chronic HIFa activation. In Aim 3, I propose to test the role of DEPP1 in ischemic
cardiomyopathy animal models. These studies will contribute to the understanding of how heart failure inhibits
FAO and identify a novel mechanism in heart failure.
I am a biologist with a background in metabolism and nutrient sensing, applying for a K99 award with the
long-term goal of becoming a tenure-track, independent laboratory investigator. I envision developing a research
program focused on how the common pathophysiology of limited oxygen availability regulates metabolism at the
cellular, tissue, and organismal level to ultimately harness that knowledge to develop new therapies for ischemic
diseases, such as heart failure and stroke. During my proposed K99 research training, I will perform mentored
research in the lab of Dr. William Kaelin at the Dana-Farber Cancer Institute (DFCI), a world’s expert in oxygen
sensing. In the K99 phase of this award, I will focus on identifying the mechanism by which DEPP1 mediates
hypoxia-induced peroxisome loss. As I transition into the R00 phase of this award, I will determine how
maintaining peroxisome function reduces cardiac death during ischemia and test the role of DEPP1 in animal
models of ischemic cardiomyopathy. I have assembled an expert scientific advisory committee to help guide my
development including: Dr. Bruce Spiegelman (DFCI/HMS), Dr. Jean Schaffer (Joslin/HMS), Dr. Christine
Seidman (HMS), and Dr. John Asara (BIDMC/DFCI). I believe that training at DFCI, a world-class clinical and
research environment, along with additional coursework and conferences will help me achieve my long-term
career goals.
