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

描述(申请人提供)：本提案的主要研究员王欣博士是布里格姆妇女医院和哈佛医学院的神经外科讲师。这项建议概述了王博士研究从筛选治疗亨廷顿病的新药(她目前的顾问项目)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R01级资金。这项建议的主要导师罗伯特·弗里德兰德博士目前是一位独立的临床科学家，在神经疾病的新药测试和治疗领域拥有广泛的出版经验，是公认的领导者。共同导师布鲁斯·克里斯托博士是线粒体功能障碍和线粒体通透性转变方面的专家，因为它们与细胞程序性死亡有关。共同导师迈克尔·莫斯科维茨博士是不同脑缺血模型领域的世界知名专家。一个由Friedlander博士、Kristal博士和Moskowitz博士以及其他五位科学家(Connolly博士、Stein博士、Glicksman博士、Li博士和Cudkowicz博士)组成的导师委员会将作为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)是进行基础和临床研究的世界级科学机构。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释放的抑制剂和11种线粒体通透性转变(MPT)的抑制剂。她将选择这些候选药物中最具神经保护作用的八种药物，在两种人类疾病的小鼠模型上进行测试：R6/2转基因菌株，其症状类似于亨廷顿病(HD)和大脑中动脉闭塞(MCAO)的C57BL/6模型中风。此外，王博士还将评估新确定的候选药物发挥其有益作用的分子机制。如初步结果部分所示，王博士已经证明了甲唑胺和褪黑素成功地抑制了细胞色素c的释放，从而阻止了神经细胞的死亡。这种分子效应与这些药物在中风小鼠模型中缩小梗塞范围和减少神经损伤的能力有关。她还提供了关于去甲替林和异丙嗪的神经保护作用的数据，这两种化合物可以抑制MPT。这些在培养细胞和小鼠身上进行的实验的最终目标是为HD和中风患者的临床试验提供参数。由于所有正在测试的化合物目前都在临床上使用(用于治疗其他综合症！)，它们最终在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.