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

我的职业目标是成为生物医学科学领域的独立调查员， 为这一领域做出有意义的贡献，帮助推进我们的知识和治疗 心血管疾病的治疗策略。更直接的是，我的目标是从 博士后研究员到一个独立的研究职位。在我的优秀设施 导师的实验室，加上医学院系的核心设施，以及 研究副院长的支持提供了一个出色的环境， 来进行这次训练。我的培训和研究计划强调持续发展 为最终过渡提供便利。这将通过一个 包括教学科学培训、指导委员会和 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重塑对 心肌应力持续增加。这包括成为技术能力， 对我来说是新的，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技能，如血液灌注分离 心脏准备本文详细介绍的建议旨在提供一个多方面的 实验方法来检验假设：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。这将是 使用三个特定目的进行检查：1）确定CGRP是否诱导P物质介导的 心肌肥大细胞的成熟和活化，导致心肌重塑; 2） 以确定类胰蛋白酶激活PAR-2是否导致心脏肥大细胞成熟， 激活以及这是否由CGRP/P物质介导;以及3）确定是否 白三烯是肥大细胞介导心肌重塑的机制。

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 Pmediated 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.