Alpha-1-Adrenergic Receptor Subtypes in the Cells of the Human Heart

描述（由申请人提供）：该提案概述了一个5年的培训计划，旨在为申请人提供工具，以培养他作为一名专注于转化性心力衰竭（HF）研究的学术研究者的成功。他完成了内科和心脏病学的严格临床培训，并在过去两年中在导师的实验室获得了分子心脏病学的经验。他现在准备在学术医学事业，并提出的方案提供了一个特殊的机会，以促进他的发展成为一个独立的医生和科学家。导师Paul Simpson博士将监督该项目和申请人的职业发展。Simpson博士在分子心脏病学领域备受尊敬，并因其对心脏肥大和α -1肾上腺素能受体（AR）生物学的理解做出的贡献而享誉国际。他也是一位训练有素的心脏病专家，指导了许多内科科学家的成功发展，因此他是这个项目的完美导师。UCSF是一个理想的培训环境，提供生物医学科学几乎所有领域的专业知识，并且该机构对申请人作为独立研究者的发展有着深刻的承诺。该研究计划自然源于申请人最近的新工作，即确定人类心脏中3种α -1- ar亚型的组织分布。来自动物研究的大量数据，包括导师创建的敲除小鼠模型，表明α - 1a和α - ib亚型在心脏中发挥有益作用并保护心力衰竭。令人惊讶的是，人类心脏α -1- ar亚型的功能尚不清楚，α -1- ar从未在人类心脏细胞中进行过研究。为了解决这些知识上的重大差距，我们提出以下3个具体目标：(1)维护和扩大UCSF/San Francisco VA人类心脏组织库；(M)鉴定来自非衰竭和衰竭人类心脏的肌细胞和成纤维细胞中的α -1- ar亚型，并使用分离细胞和全组织模型测试其功能；（三）鉴定人冠状动脉平滑肌和内皮细胞中功能性α -1- ar亚型。总的来说，这些目标将建立对人类心脏α -1- ar生物学和心衰机制的更广泛理解。该培训计划将为申请人提供宝贵的技能，使他能够使用人体系统来测试动物模型中产生的假设，并将为成功从事转化性心衰研究奠定基础。相关性：来自细胞和动物研究的大量数据表明，α -1肾上腺素能受体（ARs）在心脏中发挥有益作用并防止心力衰竭（HF），但对这些受体在人类心脏中的作用知之甚少。心衰在美国是一个主要的临床问题，迫切需要新的治疗方法。这项工作将大大扩展我们对人类心脏α -1- ars的认识，并对该项目的长期目标至关重要，该目标是开发针对α -1- ars的心力衰竭新疗法。（摘要结束）

DESCRIPTION (provided by applicant): This proposal outlines a 5-year training plan designed to equip the applicant with tools that will foster his success as an academic investigator with a focus on translational heart failure (HF) research. He has completed rigorous clinical training in both internal medicine and cardiology and has spent the past two years acquiring experience in molecular cardiology in the mentor's laboratory. He is now poised for a career in academic medicine, and the proposed program offers an exceptional opportunity to promote his development into an independent physician-scientist. The mentor, Dr. Paul Simpson, will oversee the project and the career development of the applicant. Dr. Simpson is highly respected in the field of molecular cardiology and internationally-recognized for his contributions to our understanding of cardiac hypertrophy and alpha-1-adrenergic receptor (AR) biology. He also is a trained cardiologist who has guided the successful development of many physician-scientists, hence he is a perfect mentor for this project. UCSF is an ideal setting for the proposed training program, offering expertise in nearly every area of biomedical science, and there is a deep commitment from the institution to the development of the applicant as an independent investigator. The research plan follows naturally from the applicant's recent novel work identifying the tissue distribution of the 3 alpha-1-AR subtypes in the human heart. Abundant data from animal studies, including knockout mouse models created by the mentor, show that the alpha-1 A and alpha-IB subtypes play beneficial roles in the heart and protect against HF. Surprisingly, the function of the human cardiac alpha-1-AR subtypes is unknown, and alpha-1-ARs have never been studied in human heart cells. To address these significant gaps in our knowledge, we propose the following 3 Specific Aims: (I) Maintain and expand the UCSF/San Francisco VA Human Heart Tissue Bank; (M) Identify the alpha-1-AR subtypes in myocytes and fibroblasts from non-failing and failing human hearts, and test their function using isolated cell and whole tissue models; (III) Identify the functional alpha-1-AR subtypes in human coronary smooth muscle and endothelial cells. Collectively these Aims will establish a broader understanding of human cardiac alpha-1-AR biology and the mechanisms of HF. This training program will provide the applicant with valuable skills that will allow him to use human systems to test hypotheses generated in animal models and will serve as the foundation for a successful career in translational HF investigation. RELEVANCE: Abundant data from cell and animal studies show that alpha-1-adrenergic receptors (ARs) play beneficial roles in the heart and protect against heart failure (HF), but little is known about these receptors in the human heart. HF is a major clinical problem in the US, and new treatments are badly needed. The proposed work will expand significantly our knowledge of alpha-1-ARs in the human heart and is essential to the long-term aim of the project, which is the development of a novel therapy for HF targeting alpha-1-ARs. (End of abstract)