Thursday, November 21, 2024
11/21/2024
Project Summary Our long term goal is to identify cellular and molecular mechanisms responsible for fasting-induced cardioprotection. Excessive calorie intake leads to increased risk for cardiovascular disease. On the contrary, intermittent fasting and caloric restriction can enhance cardiovascular health. Intensive research has focused on developing drugs that mimic the health-promoting effects of fasting without actually reducing food intake. However, the cardioprotective mechanisms remain speculative, making it hard to design mimetics for harnessing the full benefits of fasting. Mitochondrial autophagy or mitophagy is the process in which mitochondria are specifically delivered to and degraded in the lysosomes. Mitophagy has been shown to play an important role in maintaining cardiac homeostasis under various conditions. However, it remains completely unknown whether mitophagy is beneficial to the heart during fasting. Our preliminary studies showed that fasting accelerated mitophagy flux in the heart as determined by multiple measurements including a novel dual fluorescent mitophagy reporter. Although cardiac function was normal after 1-day fasting, it was impaired by 2-day starvation. Together, these results not only demonstrate the ability of fasting to induce mitophagy in the heart but also suggest a potential role of mitophagy in modulating cardiac function during fasting. We hypothesize that an appropriate level of mitophagy is essential for maintaining cardiac homeostasis during fasting-induced energy crisis. This hypothesis will be tested in two specific aims. Using genetically modified mice with reduced mitophagy in the heart, Aim 1 will investigate whether reducing cardiac mitophagy will lead to an accumulation of dysfunctional mitochondria, exacerbating fasting-induced cardiac injury. A novel mitophagy reporter will be used to directly visualize and quantify mitophagy in the heart. The relative importance of two mitophagy pathways, namely, Parkin and FUNDC1, in maintaining cardiac homeostasis during fasting will be determined. Using transgenic mice overexpressing Parkin or FUNDC1, Aim 2 will determine if increasing mitophagy is sufficient to enhance the degradation and recycling of dysfunctional mitochondria, rendering the heart resistant to fasting-induced injury. Successful completion of the proposed study will provide novel insight into the signaling mechanisms that mediate the cardioprotective effects of fasting and facilitate the targeted-design of effective mimetics to harness the power of fasting for preventive and therapeutic intervention in heart disease. This R15 grant will also have a very positive impact on the research environment and student learning at our institution by supporting the conduct of significant research and by engaging students of all levels in the research activities.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
