Neuro-immune Modulation of Cardiac Mast Cell-Mediated Myocardial Remodeling

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DESCRIPTION (provided by applicant): Project Summary/Abstract My career goal is to become an independent investigator in the biomedical science field and to make meaningful contributions to this field that help advance our knowledge and treatment strategies for cardiovascular disease. More immediately my aim is to make the transition from postdoctoral fellow to an independent research position. The excellent facilities within my Mentor's laboratories, coupled the School of Medicine Departmental core facilities, as well as the support from the Associate Dean of Research provide an outstanding environment in which to undertake this training. My training and research plans emphasize the continual progression towards independence facilitating the eventual transition. This will be achieved through a number of approaches including didactic scientific training, a mentoring committee and set yearly goals. The proposed research plan is designed to provide molecular, cellular, tissue and whole animal techniques for the investigation of myocardial remodeling in response to a sustained increase in myocardial stress. This includes becoming competent in techniques that are new to me such as neuronal and fibroblast cell cultures, co-cultures, flow cytometry, as well as continuing to develop my skills in familiar techniques such as the blood-perfused isolated heart preparation. The proposal detailed herein is designed to provide a multifaceted experimental approach to examine the hypothesis that: myocardial remodeling, secondary to elevated myocardial stress, involves PAR-2-mediated stimulation of neuropeptides, which induce mast cell production of leukotrienes leading to myocardial remodeling. This will be examined using three specific aims: 1) to determine whether CGRP induces substance P- mediated maturation and activation of cardiac mast cells, leading to myocardial remodeling; 2) to determine whether tryptase activation of PAR-2 causes cardiac mast cell maturation and activation and whether this is mediated by CGRP/substance P; and 3) to determine whether leukotrienes are a mechanism by which mast cells mediate myocardial remodeling. PUBLIC HEALTH RELEVANCE: In heart failure, the heart enlarges until it can no longer effectively pump sufficient amounts of blood around the body. This proposal will investigate the causes that initiate this enlargement. Once the causes are identified, drugs can be developed to treat this problem.