Discovery and Development of Therapeutic Genes for CHF

这项名为“CHF治疗基因的发现和开发”的计划项目授予竞争性续签申请的目的是使VMRF和UCSD的一些科学家能够维持一个有效、互动和相辅相成的基础和翻译研究计划，以促进充血性心力衰竭(CHF)和其他心血管疾病的治疗基因的发现和开发。该计划将促进新的治疗基因从发现到临床应用的过渡。该模型将发现性研究与实用的“街头智慧型”临床前开发相结合。成功实现我们的目标将需要独立但高度整合的项目，这些项目包含适当比例的发现研究和专注的临床前开发，一个完善的翻译生理学核心，以及一个由VMRF和UCSD内科科学家在理想环境中组成的互动小组。我们的目标是识别、执行机械性的临床前研究，并最终启动有前景的候选基因的临床试验。我们计划的优势包括：i)我们在与NHLBI目标相关的学科中拥有广泛的专业知识；2)从长凳科学到使用高保真心血管疾病动物模型进行转化性研究的方法的新颖性；以及3)我们以前成功地从发现到推出临床基因治疗试验的调控途径。我们的计划侧重于治疗(或避免心力衰竭)的基本机制，包括三个项目：项目1(哈蒙德博士)将开发和测试独特的AC相关蛋白质，作为临床CHF的治疗剂。项目2(Roth博士)将专注于CAVELLIN-3和线粒体功能在CHF病理生理学和治疗中的影响；项目3(Dillmann博士)将使用基因转移来减弱钙相关蛋白的不利糖基化，并解决CHF中的线粒体异常。四个核心将支持该计划：数字成像(Farquhar博士)、矢量制作(宫原博士)、翻译系统(Hammond博士)和临床与行政(Hammond博士)。

The purpose of this Program Project Grant competitive renewal application entitled "Discovery & Development of Therapeutic Genes for CHF" is to enable a number of scientists at VMRF and UCSD to maintain an efficient, interactive and mutually reinforcing program of basic and translational research to promote the discovery and development of therapeutic genes for congestive heart failure (CHF) and other cardiovascular diseases. The Program will facilitate the transition from discovery to clinical application of new therapeutic genes. This model combines discovery research with practical "street-smart" preclinical development. Successfully attaining our goals will require separate but highly integrated Projects that contain the proper proportions f discovery research and focused preclinical development, an accomplished translational physiology Core, and an interactive group of VMRF and UCSD physician-scientists in an ideal environment. Our goals are to identify, perform mechanistic preclinical studies, and eventually to launch clinical trials of promising candidate genes. Strengths of our Program include: i) the breadth of our expertise across disciplines relevant to the goals of the NHLBI; 2) the novelty of approaches ranging from bench science to translational studies using high-fidelity animal models of cardiovascular diseases; and 3) our previous success navigating the regulatory pathway from discovery to launching clinical gene therapy trials. Our Program, which is focused on fundamental mechanisms by which the failing heart can be treated (or heart failure avoided), includes three Projects: Project 1 (Dr. Hammond) will develop and test unique AC-related proteins as therapeutic agents for clinical CHF. Project 2 (Dr. Roth) will focus on the impact of cavelolin-3 and mitochondrial function in the pathophysiology and treatment of CHF; and Project 3 (Dr. Dillmann) will use gene transfer to attenuate adverse glycosylation of calcium-related proteins and resolve mitochondrial abnormalities in CHF. Four Cores will support the Program: Digital Imaging (Dr. Farquhar); Vector Production (Dr. Miyanohara); Translational Systems (Dr. Hammond) and Clinical & Administrative (Dr. Hammond).