This proposal describes a five year training program to enable the applicant to expand her scientific knowledge, advance her technical skills, and establish independence from her primary mentor. In addition to the primary mentor the applicant has a co-mentor to help achieve the goals of this proposal. The overall scientific objectives are to address the role of mitofusin-dependent mitochondrial remodeling in endothelial cell function, and how this activity is perturbed by metabolic disease. An intact vascular endothelium is critical for the proper functioning of tissues such as muscle, heart and brain. Although mitochondria are the primarily energy generators in a cell, endothelial cell mitochondria appear to function more as biological sensors and signaling intermediates. Therefore, understanding how mitochondria regulated endothelial function is critical to our understanding of how vascular and metabolic diseases induce endothelial dysfunction. Based on the premise that a proper balance in Nitric Oxide (NO), Reactive Oxygen Species (ROS), or Ca2+ signaling is vital for normal mitochondrial function/signaling and a proper functioning vascular endothelium, the PI has developed a novel hypothesis wherein the mitochondrial shaping proteins;Mfn1 and Mfn2 perform crucial roles in the maintenance of proper architecture and function of the mitochondrial compartment in endothelial cells and that their ablation will affect endothelial function, particularly under conditions of metabolic stress. Emerging evidence indicates that ablation of both Mfn1 and Mfn2 is essential for maintaining mitochondrial morphology, cell differentiation, migration and survival under conditions of stress, and generation of mitochondrial-derived ROS and their impact on intracellular signaling in endothelial cells. Here, the PI will attempt to establish mitofusins as novel regulators of endothelial mitochondrial signaling and endothelial cell function.
In Aim 1, the applicant will determine the mechanisms through which mitofusins regulate EC migration. Next, using mouse reagents that ablate Mfn1 and/or Mfn2 proteins in endothelial cells, the PI will evaluate whether mitofusins affect endothelial cell function at baseline and in response to diet-induced metabolic stress (Aim 2). Lastly, the applicant will evaluate whether mitofusins regulate the ability of the vasculature to revascularize following hind limb ischemia (Aim 3). Data garnered from such innovative studies may provide a new insight to disease processes that are associated with disordered blood vessel growth. The goals of this proposed research are consistent with that of the MRSDA because it will provide me with training in the area of mouse genetic models through the development of strains that specifically ablate Mfn1, Mfn2 or both in the vascular endothelium, and it will allow me to mature my research effort into an area of study that is relatively unexplored (vascular metabolism), thereby providing a niche to develop an independent research program. The PI's long-term goal is to establish an independent laboratory in an academic environment. The resources available to the PI at BUSM are sufficient to achieve this goal.
Diseases such as diabetes and arthrosclerosis are characterized by mitochondrial and endothelial cell dysfunction. Understanding the biology of endothelial mitochondria is critical to our understanding of how metabolic dysfunction contributes to vascular diseases. By using mouse models to understand the role of mitochondrial dynamics in endothelial cell function, our studies might provide new insights and allow the development of new strategies to combat diseases associated with endothelial dysfunction.