PRDM16 and Cardiomyopathies
PR domain containing 16 (PRDM16) is a transcriptional regulator involved in several biological processes. Our group recently demonstrated that the loss of the PRDM16 locus in humans affected by chromosome 1p36 deletion syndrome is sufficient to cause two types of cardiomyopathies: non-compaction cardiomyopathy (NCM) and dilated cardiomyopathy (DCM). Our lab is currently investigating the mechanisms by which loss of Prdm16 causes these cardiac phenotypes in a sex-dependent manner, as female sex confers a higher risk for DCM and mortality in individuals lacking PRDM16.We and others have shown that cardiac deficiency of Prdm16 in mice causes NCM, DCM, and heart failure, and we are currently working to determine the biological mechanisms driving this sex-specific increase in cardiac mortality risk.
Mitochondrial Energetics and Cardiac Remodeling
Heart failure with preserved ejection fraction (HFpEF) has recently emerged as an insidious and increasingly prevalent heart failure phenotype now accounting for over 50% of heart failure mortality. HFpEF often occurs in the context of hypertension and systemic metabolic dysregulation and presents with diastolic dysfunction, ventricular hypertrophy, and myocardial fibrosis. While cardiac structural remodeling and bioenergetic changes are two well-known hallmarks of advanced heart disease, the mechanistic and temporal links between early metabolic changes, bioenergetics perturbations, and cardiac structural remodeling in HFpEF remain unclear.
A deeper understanding of the temporal and causal cascades in the early pathogenesis of HFpEF would present attractive therapeutic targets for early intervention, which would greatly benefit a growing population of HFpEF patients with of yet very limited treatment options. Thus, our ongoing research seeks to elucidate the temporal and causal interplay of cardiac mitochondrial bioenergetics and myocardial structural remodeling to determine the causative drivers and downstream consequences of the pathogenic HFpEF cascade.
Autophagy in Health and Disease
Autophagy is a conserved homeostatic mechanism used by many cells and organisms to eliminate unwanted and dysfunctional proteins and organelles. It is also used to recycle cellular components and molecules to generate energy during starvation. The Boudina lab has extensively studied this pathway in the context of diabetic cardiomyopathy and diet-induced obesity. One of our ongoing projects is investigating the role of liver autophagy in the maintenance of blood glucose levels during fasting. Using conditional knockout of the autophagy machinery (Atg3 and Atg16L), we examine the mechanisms linking autophagy and glucose release from the liver. The goal is to manipulate liver autophagy to regulate blood glucose levels in the setting of type 2 diabetes.
Along this line of research, we recently identified the autophagy adaptor protein p62 or sequestosome 1 as a key player in redox homeostasis in the heart. The absence of p62 in the heart results in Nrf2 degradation, increased ROS, and age-associated cardiac dysfunction. Similarly, we found that p62 deficiency in the heart reduced HIF-1a stabilization and exacerbated cardiac dysfunction during hypoxia. We seek to understand how p62 stabilizes Nrf2 and HIF-1a in the heart, as this information could be used to develop p62 mimetics for the treatment of ischemic heart disease.
Adipose Tissue Cellularity and Adipogenesis
Not all obese patients are equally affected by metabolic dysregulation. In fact, metabolically healthy obese patients can be distinguished from metabolically unhealthy obese patients by the number and the size of their adipocytes despite similar body mass index (BMI). Storing fat in new adipocytes, which requires adipogenesis, may be a beneficial way to safely store excess fat and maintain health. The goal of this project is to discover novel regulators of adipogenesis both in humans and mice. Using single cell sequencing, we and others have begun to parse out the cellular progenitors that differentiate into adipose tissue. We recently identified new factors that may modulate adipogenesis in vitro and in vivo, and we aim to understand the involve mechanisms of action. Characterizing these cells and identifying factors that facilitate their communication may aid the understanding of adipose tissue expansion, providing attractive therapeutic targets for obesity intervention.