Identification of Novel Drugs against Huntington's Disease and Cerebral Ischemia

描述（由申请人提供）：本提案的主要研究者Xin Wang博士是布里格姆妇女医院和哈佛医学院的神经外科讲师。该提案概述了王博士的研究从筛选治疗亨廷顿病的新药（她目前的导师项目）到寻找减少缺血性中风影响的化合物的指导过渡。后一项调查将是她独立学术活动的主题。从那时起，她将申请R 01级资助。Robert Friedlander博士目前是一位独立的临床科学家，在神经系统疾病的新药测试和治疗领域拥有丰富的已发表经验。共同导师布鲁斯克里斯塔尔博士是线粒体功能障碍和线粒体渗透性转变方面的专家，因为它们与程序性细胞死亡有关。共同导师Michael Moskowitz博士是不同脑缺血模型领域的世界知名专家。一个由弗里德兰德博士、克里斯塔尔博士和莫斯科维茨博士以及其他五位科学家（康诺利博士、斯坦博士、格里克斯曼博士、李博士和库德科维奇博士）组成的导师委员会将担任王博士的顾问委员会，并将仔细监督王博士的进展。开展拟议工作的环境（哈佛医学院）是一个世界级的科学机构，在那里进行基础和临床研究。在这个项目中，王博士将在两个培养神经元系统中筛选21种细胞色素c释放抑制剂和11种线粒体通透性转换（mPT）抑制剂。她将选择这些候选药物中最有效的八种用于在两种人类疾病小鼠模型中进行测试：R6/2转基因品系，其综合征类似于亨廷顿病（HD）和C57 BL/6模型中的大脑中动脉闭塞（MCAO）中风。此外，王博士将评估新发现的候选药物发挥其有益作用的分子机制。如实验结果部分所述，Wang博士已经证明醋甲唑胺和褪黑素成功抑制细胞色素c释放，从而阻断神经元细胞死亡。这种分子效应与这些药物在中风小鼠模型中减少梗死面积和减少神经损伤的能力相关。她还提供了去甲替林和异丙嗪（抑制mPT的化合物）的神经保护作用的数据。在培养细胞和小鼠中进行这些实验的最终目标是为患有HD和中风的患者的临床试验提供参数。由于所有被测试的化合物都在目前的临床使用中（用于治疗其他综合征！），它们在最终的人体试验中应该是安全的。

DESCRIPTION (provided by applicant): The principal investigator for this proposal, Dr. Xin Wang, is an Instructor of Neurosurgery at Brigham and Women's Hospital and Harvard Medical School. This proposal outlines a mentored transition of Dr. Wang research from screening novel drugs for Huntington's diseases (her current advisor's project) to searching for compounds that decrease the impact of ischemic stroke. The latter investigation will be the subject of her independent academic activity. From then on she will apply for R01 level funding. The primary mentor for this proposal, Dr. Robert Friedlander, is currently an independent clinical scientist and recognized leader with extensive published experience in the area of novel drug testing and therapy for neurological diseases. The co-mentor, Dr. Bruce Kristal, is an expert in mitochondrial dysfunction and the mitochondrial permeability transition as they relate to programmed cell death. The co-mentor, Dr. Michael Moskowitz is a world-renown expert in the area of different models of cerebral ischemia. A mentor committee consisting of Drs. Friedlander, Kristal and Moskowitz and five other scientists (Drs. Connolly, Stein, Glicksman, Li and Cudkowicz) will serve as the advisory committee for Dr. Wang and will carefully supervise Dr. Wang' progress. The environment in which the proposed work will be carried out (Harvard Medical School) is a world class scientific institution where both basic and clinical researches are conducted. In this project, Dr. Wang will screen the twenty-one inhibitors of cytochrome c release and eleven inhibitors of the mitochondrial permeability transition (mPT) in two systems of cultured neurons. She will select the eight most potently neuroprotective of these candidate drugs for testing in two mouse models of human disease: the R6/2 transgenic strain whose syndrome resembles Huntington's disease (HD) and middle cerebral artery occlusion (MCAO) in C57BL/6 that models stroke. Furthermore, Dr. Wang will evaluate the molecular mechanisms by which the newly identified candidate drugs exert their beneficial effects. As presented in the Preliminarily Result section, Dr. Wang has demonstrated that methazolamide and melatonin successfully inhibit cytochrome c release, thereby blocking neuronal cell death. This molecular effect correlates with these drugs' ability to decrease infarct size and reduced neurological impairment in the mouse model of stroke. She also presents data on the neuroprotective effects of nortriptyline and promethazine, compounds that inhibit mPT. The ulimate goal of these experiments in cultured cells and in mice is to suggest the parameters for clinical trials on patients who suffer HD and stroke. As all the compounds being tested are in current clinical use (to treat other syndromes!), they should be safe for eventual human trials.