Role of protein acetylation in Huntington's disease

亨廷顿病(HD)和其他扩张性聚谷氨酰胺疾病是晚期的- 突变体中谷氨酰胺重复序列的扩大引起的首发神经退行性疾病 蛋白。目前，对于这些令人痛苦和致命的疾病，还没有治愈或有效的治疗方法。 扩大的谷氨酰胺重复序列的致病靶点尚不清楚。我们发现， 亨廷顿蛋白的聚谷氨酰胺结构域(Htt)结合并抑制几种 乙酰转移酶(如CBP、p300和P/CAF)并降低细胞中乙酰化组蛋白的水平 文化。 我们已经开发并使用了两个HD的果蝇模型来测试 神经病理可能是由于乙酰化和转录水平降低所致。我们发现 通过两个独立的机制来抑制脱乙酰化过程。遗传上的或 药理上(HDAC抑制剂)降低致死率并抑制光感受器神经元 退化。这些结果强烈暗示了乙酰化在致病过程中的状态。 由于包括SAHA在内的几种HDAC抑制剂目前已被FDA批准用于其他临床 设置或处于I期临床试验中，HDAC抑制剂现在可以被认真考虑为 HD及相关疾病的潜在治疗药物。这是早期的案例之一。 在果蝇模型中已经确定了潜在有用的药理药物 疾病。 在这里，我们建议使用果蝇模型来扩展这些研究。在苍蝇和 人类有组蛋白乙酰转移酶(HAT)和组蛋白脱乙酰基酶(HDAC)家族 基因(-11个HATS和~9个HDAC相关基因)。在这个项目中，我们将确定是否所有或 这些基因中只有一些与聚谷氨酰胺的发病机制有关，我们将确定 贡献是否具有累加性。这些数据将提高我们对基因和 发病机制的分子基础，他们将为治疗确定新的靶点，他们将 揭示在HAT/HDAC循环中针对多种酶的联合治疗是否可能 要有效率。 PERFORMANCSEITE(S)(组织机构，单位，单位) 加州大学欧文分校，加利福尼亚州欧文，92697 关键人员见说明。根据需要在页面上使用conl/nua_/以如下所示的格式提供所需的信息。 从首席调查员开始。按字母顺序列出所有其他关键人员，姓氏在前。 名称组织角色项目 首页--期刊主要分类--期刊细介绍--期刊题录与文摘--文摘内容 莱斯利·M·汤普森博士，加州大学欧文分校精神病学和哼唱行为博士 Namita Agrawal博士开发和细胞生物学，加州大学欧文分校研究生研究员 塔马斯·卢卡索维奇博士开发与细胞生物学，加州大学欧文分校50%专业研究员 加州大学欧文分校研究生马丁·希克斯：细胞生物学 加州大学欧文分校初级专家Lazlo Bodai开发和细胞生物学67% 加州大学欧文分校初级专家Judit Pallos开发与细胞生物学67% 披露Perm/ss/On声明。仅适用于$BIPJSTTR。请参阅说明。[]是[]否 ，PHS 398(05/01版)第_2页表格第2页+ 使用_-英寸边距。请在申请表底部连续编号页码。请勿使用后缀3a、3b。 Pdndp调查人员/Pdrogreract(mLoarst，第一，中间)：Marsh。J.劳伦斯 必须在每张打印页和每张续页的顶部提供主要调查员/项目总监的姓名。 字体密度和大小必须符合PHS 398说明书中提供的限制和规格。 研究补助金 目录 页码 主页.......................................................................................................................1 描述，

Huntington's disease (HD) and other expanded polyglutamine diseases are late- onset neurodegenerative diseases caused by expansion of a glutamine repeat in the mutant protein. Currently, no cure or effective treatment for these agonizing and lethal diseases exists. The pathogenic target of the expanded glutamine repeat is unknown. We find that the polyglutamine domain of Huntingtin (Htt) binds to and inhibits the activity of several acetyltransferases (e.g.CBP, p300, and P/CAF) and reduces the level of acetylated histones in cell culture. We have developed and used two Drosophila models of HD to test the possibility that neuropathology may result from reduced levels of acetylation and transcription. We find that inhibition of the deacetylation process by two independent mechanisms Le. genetically or pharmacologically (HDAC inhibitors) reduces lethality and arrests photoreceptor neuron degeneration. These results strongly implicate the state of acetylation in the pathogenic process. As several HDAC inhibitors, including SAHA, are currently FDA approved for use in other clinical settings or are in Phase I clinical trials, HDAC inhibitors can now be seriously considered as potential therapeutic agents for HD and related diseases. This represents one of the early cases where potentially useful pharmacologic agents have been identified in a Drosophila model of disease. Here we propose to extend these studies using the Drosophila model. In both flies and man there are families of HAT (Histone Acetyl Transferase) and HDAC (Histone DeACetylase) genes (-11 HATs and ~9 HDAC related genes). In this project, we will determine whether all or just some of these genes are relevant to polyglutamine pathogenesis and we will determine whether contributions are additive. These data will improve our understanding of the genetic and molecular basis of pathogenesis, they will identify new targets for therapeutics and they will reveal whether combination therapies targeted at multiple enzymes in the HAT/HDAC cycle might be effective. PERFORMANCSEITE(S)(organizatiocnit,ys, tate) University of California, Irvine, Irvine, CA 92697 KEY PERSONNEL See instruc_ons. Use conl/nua_/onpages as neededto providethe requiredinformationinthe format shown below. Startwith PrincipalInvestigator. List all other key personnel in alphabetical order, last name first. Name Organization Roleon Project J. Lawrence Marsh, Ph.D. Devel.& Cell Biology, UC Irvine PI Leslie M. Thompson Ph.D. Psychiatry and Hum Behavior, UC Irvine Co-PI Namita Agrawal Ph.D. Devel.& Cell Biology, UC Irvine Post graduate researcher Tamas Lukacsovich Ph.D. Devel.& Cell Biology, UC Irvine Professional researcher 50% Martin Hicks Devel.& Cell Biology, UC Irvine graduate student Lazlo Bodai Devel.& Cell Biology, UC Irvine Junior specialist 67% Judit Pallos Devel.& Cell Biology, UC Irvine Junior specialist 67% Disclosure Perm/ss/on Statement. Applicable tO$BIPJSTTR Only. See instructions. [] Yes [] No , PHS 398 (Rev. 05/01) Page_2 Form Page 2 + Use_-inch MARGINS. Number pages consecutivelyat the bottomthroughoutthe application.Do not use suffixessuchas 3a, 3b. PdndpInavl estigator/PDroigreract(mLoarst, first,middle): Marsh. J. Lawrence The name of the principalinvestigator/programdirectormust be providedat the top of each printedpage and each continuationpage. Type density and size must conform to limits and specifications provided in the PHS 398 Instructions. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page ..................................................................................................................................... 1 Description,