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Molecular Pathogenesis & Therapy for Critical Limb Ischemia

Institution: University of California, San Francisco
Investigator(s): Rong Wang, Ph.D.
Award Cycle: 2019 (Cycle 28) Grant #: 28IR-0067 Award: $935,403
Subject Area: Cardiovascular and Cerebrovascular Disease
Award Type: High Impact Research Project Award

Initial Award Abstract

The proposed study aims to seek novel treatment strategies for peripheral artery disease (PAD). PAD occurs when the arteries that supply blood to the arms and legs are blocked by plaque build-up, decreasing blood flow to the extremities. PAD affects more than 10 million Americans over the age of 65.  Cigarette smoking increases the risk of developing PAD by 4-fold, and lowers the age of onset by 10 years. About 200,000 PAD patients develop to a more severe condition, critical limb ischemia (CLI), which can result in limb amputation or death. PAD is currently treated through surgical intervention, but complications and failures from these surgeries occur frequently. Further, many PAD patients are poor candidates for these interventions. Therefore, developing better treatment options for PAD is urgent.  My lab studies therapeutic arteriogenesis, an innovative, non-invasive strategy to develop novel molecular therapies for PAD. To restore blood flow after artery blockage, small dormant arteries around the blockage must enlarge. Arteriogenesis, the ability to enlarge these dormant arteries, holds promise to rescue affected tissues. We have discovered that a gene encoding a protein on the surface of blood vessel wall cells can allow mice to recover from experimental arterial blockage better than mice without this gene. We will test the efficacy of this gene as a molecular stimulator for therapeutic arteriogenesis, particularly in old mice exposed to cigarette smoke. Using state-of-the-art techniques, we will test if this gene promotes dormant arteries around the blockage to acutely expand following arterial blockage, and then to grow larger to serve as long-term, durable, conduit artery replacements for the blocked artery. Determining the mechanism through which this gene enhances recovery from artery blockage will aid in our drug development effort to treat PAD. Finally, we will also test if the level of this gene is lower in amputated lower limbs from human CLI amputees compared to normal limbs from trauma amputees, paving the way for drug development. PAD and other cardio- and cerebrovascular diseases, such as heart attack and stroke, share the similar underlying cause of arterial narrowing and lack of blood flow. Results from this proposed work may have significant therapeutic implications for many tobacco-related diseases including heart attack and stroke.