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DiaComp Funded Abstracts Pilot & Feasibility Funding Programs



Pilot & Feasibility Program Application Abstract
Identifying Alterations in Mitochondrial Dynamics Associate
Eva Feldman   (Ann Arbor, MI)
Diabetes is a growing epidemic, affecting more than 387 million individuals worldwide. Up to 60% of diabetic patients have diabetic neuropathy (DN), a debilitating microvascular complication that results in the progressive loss of sensory nerve function in the extremities. Despite the deleterious impact of DN, therapies for the disease are limited to symptomatic relief. To develop effective treatments that specifically target DN, a mechanistic understanding of molecular pathways that result in neurological dysfunction associated with diabetes is needed. Recent evidence suggests that dyslipidemia, rather than hyperglycemia, is the clinical parameter that correlates with the progression of DN. Since metabolic pathways converge on the mitochondria (Mt), these organelles play a central role in maintaining neuronal cellular function and energy homeostasis through mitochondrial (Mtl) trafficking mechanisms and endoplasmic reticulum (ER)-mediated calcium signaling pathways. However, metabolic overload associated with diabetes may result in aberrant calcium dynamics in the primary sensory neurons of the nervous system, the dorsal root ganglia (DRG), resulting in diminished Mtl trafficking and cell death induced by ER-Mt contact sites. We hypothesize that hyperlipidemia increases the level of ER-Mt contact sites in DRG neurons, creating a localized calcium flux which triggers Mtl apoptosis and halts Mtl trafficking. We will test this hypothesis by 1) evaluating the role of ER-Mt interactions in Mtl dysfunction and neuronal cell death in the DRG and sural nerve of a high fat (HF)-fed mouse model, and 2) identifying changes in calcium dynamics that impair Mtl trafficking in hyperlipidemic DRG neurons. These studies will provide important insight into the role of Mtl dynamics in DN and thereby support our long-term goal of identifying therapeutic targets that specifically improve Mtl function and restore nerve function to patients with DN.
No report available yet.