Huntington's Disease Natural Product Drug Discovery

亨廷顿病天然产物药物发现

基本信息

批准号：
8538550
负责人：
William Henry Gerwick
金额：
$ 6.2万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8538550
关键词：
Affect Algae Area Behavioral Biochemical Biochemistry Biological Assay Biological Factors Brain region Calpain Caspase Cathepsin L Cell Death Cell Line Cells Cellular Assay Chemicals Chemistry Cleaved cell Collection Corpus striatum structure Cyanobacterium Data Dementia Development Discipline Disease Drug Compounding Effectiveness Evaluation Future Gene Mutation Genetic Goals Hereditary Disease Huntington Disease Huntington gene Impaired cognition Inherited Inhibitory Concentration 50 Joints Kinetics Knowledge Laboratories Length Marines Mediating Metalloproteases Modeling Molecular Monitor Motor N-terminal Natural Product Drug Neurobiology Neurodegenerative Disorders Neurons Pathogenesis Pathology Peptide Hydrolases Pharmaceutical Preparations Phenotype Principal Investigator Process Production Protease Inhibitor Proteolysis Relative (related person)Research Screening procedure Small Interfering RNA Source Testing Therapeutic Agents Transgenic Mice Trinucleotide Repeats Western Blotting attenuation caspase-6 drug development drug discovery drug testing experience human Huntingtin protein improved in vitro testing in vivo inhibitor/antagonist marine natural product motor impairment mouse model mutant nervous system disorder neurochemistry neuron loss neurotoxic neurotoxicity novel novel therapeutics relating to nervous system small molecule

项目摘要

DESCRIPTION (provided by applicant): Huntington's Disease (HD) is a neurological disorder resulting from CAG triplet repeat genetic mutation of the IT15 gene that encodes the huntingtin protein. Extensive data in the field indicate that proteolytic fragment(s) of htt mediate the HD disease process, resulting in severe motor disturbances. The goal of this project will be to discover novel marine natural product compounds as potential therapeutic agents for Huntington's disease (HD). This project fulfills a major gap in the HD and neurodegenerative disease field for discovery of novel agents as protease inhibitors for future development of therapeutic agents for HD. Furthermore, this project uses novel marine natural products as a unique opportunity for drug discovery in the protease target area to reduce production of neurotoxic htt proteolytic fragments that participate in HD. This unique project will integrate expertise in protease biochemistry and neurobiology by Dr. Vivian Hook, marine natural products for discovery of therapeutic agents by Dr. William Gerwick, and model striatal neuronal cells, as well as transgenic mice, expressing mutant huntingtin (htt) protein of Huntington's disease by Dr. Albert La Spada at the Univ. of Calif., San Diego. The project plan will implement interdisciplinary efforts of three highly experienced laboratories in the required disciplines to discover novel protease inhibitors of huntingtin protein proteolysis as a means to reduce cellular mutant htt neurotoxicity. This project can progress at a rapid pace since the collaborating laboratories have the required expertise, and are located in close proximity to one another at UC San Diego. HD drug discovery of this project will be accomplished in two specific aims. The first aim will evaluate marine natural product compounds for inhibition of protease activities thought to be involved in HD, which includes caspase, calpain, lysosomal proteases (cathepsins L, B, and D), and matrix metalloprotease 10. Cyanobacteria algal marine natural product compounds are a rich source of potent drug molecules with unique structural diversity. In aim 2, cyanobacterial marine natural compounds will be tested in cellular assays for reduction of N-terminal htt fragments and protection from cell death, using striatal-like neuronal cells that express full-length mutant huntingtin (htt) protein, and in control cells expressing normal htt protein. Effective compounds identified from aims 1 and 2 will be prioritized by their inhibitory potencies. These compounds will be planned for a future R01 project that will conduct in vivo testing of compounds in HD mouse models for effectiveness to improve the motor impairment in HD transgenic mice. Results can indicate candidate marine natural drug compounds for HD drug development.

描述（由申请人提供）：亨廷顿氏病（HD）是一种神经系统疾病，是由CAG三胞胎重复遗传突变的IT15基因，该基因编码亨廷汀蛋白。该领域的大量数据表明，HTT的蛋白水解片段介导HD疾病过程，从而导致严重的运动障碍。该项目的目的是发现新型的海洋天然产品化合物作为亨廷顿氏病（HD）的潜在治疗剂。该项目符合HD和神经退行性疾病领域的主要差距，以发现新型药物作为蛋白酶抑制剂，用于未来开发HD治疗剂的蛋白酶抑制剂。此外，该项目使用新型的海洋天然产品作为在蛋白酶靶区域中发现药物的独特机会，以减少参与HD的神经毒性HTT蛋白水解片段的产生。这个独特的项目将纳入Vivian Hook博士在蛋白酶生物化学和神经生物学方面的专业知识，威廉·格里克（William Gerwick）博士发现治疗剂的海洋天然产品，以及模型的纹状体神经元细胞以及转基因小鼠，表达了huntington huntington（htt）huntington's Diseation of Albert labert labert labert labert lab the Un的蛋白质。圣地亚哥加州。该项目计划将在所需学科中实施三个经验丰富的实验室的跨学科努力，以发现亨廷顿蛋白蛋白蛋白蛋白蛋白水解的新型蛋白酶抑制剂，作为降低细胞突变体HTT神经毒性的手段。由于合作实验室具有所需的专业知识，因此该项目可以快速进步，并且在圣地亚哥分校彼此之间彼此相近。该项目的高清药物发现将以两个具体的目的来完成。第一个目的将评估海洋天然产物化合物，以抑制被认为与HD有关的蛋白酶活性，其中包括胱天蛋白酶，钙蛋白酶，钙蛋白酶，溶酶体蛋白酶（cantepsins L，B，B和D）和基质金属蛋白酶10。氰基菌菌菌菌菌菌具有独特的药物分量的富源源代码。在AIM 2中，使用纹状体样神经元细胞，在细胞测定中测试蓝细菌海洋天然化合物，以减少N末端HTT片段和免受细胞死亡的保护，这些神经元细胞表达全长突变体亨廷汀（HTT）蛋白，以及表达正常HTT HTT蛋白的对照细胞中。从目标1和2确定的有效化合物将由其抑制作用优先考虑。这些化合物将针对未来的R01项目计划，该项目将在HD小鼠模型中对化合物进行体内测试，以提高HD转基因小鼠的运动障碍。结果可以表明用于HD药物开发的候选海洋天然药物化合物。