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

描述（由申请人提供）：项目摘要/摘要我的职业目标是成为生物医学科学领域的独立研究者，并为这一领域做出有意义的贡献，帮助推进我们的知识和心血管疾病的治疗策略。更直接的目标是从博士后过渡到独立的研究职位。在我的导师的实验室内的优良设施，再加上医学系的核心设施的学校，以及从研究的副院长的支持提供了一个出色的环境中进行这种培训。我的培训和研究计划强调不断走向独立，促进最终的过渡。这将通过一系列方法来实现，包括教学科学培训、指导委员会和设定年度目标。拟议的研究计划旨在提供分子、细胞、组织和整体动物技术，用于研究心肌应激持续增加引起的心肌重塑。这包括在新的技术，如神经元和成纤维细胞培养，共培养，流式细胞术，以及继续发展我熟悉的技术，如血液灌注离体心脏制备的技能成为主管。本文详细介绍的建议旨在提供一个多方面的实验方法来检查假设：心肌重塑，继发于心肌应激升高，涉及PAR-2介导的神经肽刺激，诱导肥大细胞产生白三烯，导致心肌重塑。这将使用三个特定的目的进行检查：1）确定CGRP是否诱导P物质介导的心脏肥大细胞的成熟和活化，导致心肌重塑; 2）确定类胰蛋白酶激活PAR-2是否引起心脏肥大细胞的成熟和活化，以及这是否由CGRP/P物质介导;和3）确定白三烯是否是肥大细胞介导心肌重塑的机制。 公共卫生相关性：在心力衰竭中，心脏扩大，直到它不能再有效地泵送足够的血液到身体周围。这一建议将调查导致这种扩大的原因。一旦确定了原因，就可以开发药物来治疗这个问题。

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.