富含亮氨酸重复激酶2活性调节的分子基础-猫眼课题宝

富含亮氨酸重复激酶2活性调节的分子基础

批准号：

9106756

负责人：

Quyen Quoc Hoang

金额：

$57.23万

依托单位：

ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI

依托单位国家：

美国

项目类别：

财政年份：

2016

资助国家：

美国

项目状态：

已结题

起止时间：

2016-06-01 至 2020-05-31

来源：

https://reporter.nih.gov/project-details/9106756

关键词：

3-Dimensional Academia Affect Animals Ankyrins Architecture Attention Biochemical Biochemistry Biological Assay C-terminal Catalytic Domain Cell Culture Techniques Cells Collaborations Corpus striatum structure Data Dimerization Dopamine Dose Drug Industry Drug Targeting Electron Microscopy Enzymes Family Family Dasypodidae GTP Binding Genes Genetic Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Human Hydrolysis Inherited LRRK2 gene Laboratories Learning Length Link MAP Kinase Kinase Kinase Measures Modeling Molecular Mutagenesis Mutation Nature Neurodegenerative Disorders Parkinson Disease Pathogenesis Phosphotransferases Physiology Play Point Mutation Protein Kinase Proteins Regulation Research Resolution Risk Factors Roentgen Rays Role Staining method Stains Structure Testing Therapeutic Transgenic Mice Variant Work X-Ray Crystallography base genome wide association study in vitro activity in vivo protein protein interaction public health relevance structural biology therapeutic development therapeutic target transmission process

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DESCRIPTION (provided by applicant): Statement of Work. The research proposed in this multi-PI application with three PIs (Drs. Hoang, Yue and Ubarretxena) combines the efforts of three different laboratories to study the structure and activity regulation of Leucine Rich Repeat Kinase 2 (LRRK2). Mutations in this unique multi- domain enzyme have been linked with Parkinson's disease (PD) pathogenesis, and thus LRRK2 has emerged as a key therapeutic target for the treatment of this neurodegenerative disorder. The results obtained from X-ray crystal structures of the GTPase domain and the COR region carrying PD-linked mutations (Dr. Hoang component) and those obtained from the high- resolution electron microscopy 3-D models of full-length LRRK2 (Dr. Ubarretxena component) will be used to inform the biochemical, cell-based and animal studies (Dr. Yue component). In particular, we will learn how the GTPase and kinase activities in LRRK2 are coordinated and how domain-domain interactions in the enzyme, and PD-linked mutations affect these activities.

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