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

心脏肥大细胞介导的心肌重塑的神经免疫调节

• 批准号: 7787694
• 负责人: Scott P Levick
• 金额: $ 9万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7787694
• 关键词: Animals; Atrial Natriuretic Factor; Biochemical; Bladder; Blood; Calcitonin Gene-Related Peptide; Cardiac; Cardiomegaly; Cardiovascular Diseases; Cell Culture Techniques; Cell Density; Cell Maturation; Coculture Techniques; Congestive Heart Failure; Core Facility; Coupled; Data; Development; Endothelin-1; Environment; Extracellular Matrix Degradation; Fiber; Fibroblasts; Fibrosis; Fistula; Flow Cytometry; Functional disorder; Goals; Heart; Heart Transplantation; Heart failure; Hematopoietic; Hypertension; Immunologics; In Vitro; Inflammation; Inflammatory; Investigation; Knowledge; Laboratories; Left; Left Ventricular Hypertrophy; Leukotriene Production; Leukotrienes; Link; Lung; Matrix Metalloproteinases; Mediating; Mentors; Modeling; Molecular; Myocardial; Myocardium; Nerve Fibers; Neurons; Neuropeptides; Nociception; Organ; PAR-2 Receptor; Pathway interactions; Peritoneal; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Positioning Attribute; Postdoctoral Fellow; Preparation; Pump; Rattus; Regulation; Research; Research Personnel; Research Training; Science; Secondary to; Series; Skin; Stress; Substance P; Techniques; Tissues; Training; Tryptase; Ventricular; Ventricular Remodeling; abstracting; afferent nerve; career; design; immunoregulation; in vivo; interest; mast cell; medical schools; novel; pressure; public health relevance; relating to nervous system; research study; response; skills; spatial relationship; treatment strategy

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.

项目概述/摘要我的职业目标是成为生物医学领域的独立研究者，并在这一领域做出有意义的贡献，帮助我们提高心血管疾病的知识和治疗策略。更直接的目标是完成从博士后到独立研究职位的过渡。导师实验室的优秀设施，加上医学院的核心设施，以及研究副院长的支持，为我进行这项培训提供了一个出色的环境。我的培训和研究计划强调不断走向独立，以促进最终的过渡。这将通过一系列方法来实现，包括教学科学培训、指导委员会和制定年度目标。提出的研究计划旨在提供分子、细胞、组织和全动物技术来研究心肌重构对持续增加的心肌应激的反应。这包括掌握对我来说陌生的技术，如神经元和成纤维细胞培养、共培养、流式细胞术，以及继续发展我在熟悉的技术方面的技能，如血液灌注分离心脏制备。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以下假设：心肌重构，继发性心肌应激升高，涉及par -2介导的神经肽刺激，其诱导肥大细胞产生白三烯导致心肌重构。这将通过三个特定目的进行研究：1)确定CGRP是否诱导P物质介导的心肌肥大细胞成熟和激活，从而导致心肌重构；2)确定胰蛋白酶PAR-2的激活是否导致心肌肥大细胞的成熟和激活，以及这是否由CGRP/ P物质介导；3)确定白三烯是否是肥大细胞介导心肌重构的机制。