Chemical-Genetic Approaches to Define Lrrk2 Kinase Function in Parkinson Disease

定义 Lrrk2 激酶在帕金森病中功能的化学遗传学方法

• 批准号: 9129756
• 负责人: Annie E Hiniker
• 金额: $ 19.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9129756
• 关键词: Active Sites; Advisory Committees; Affect; Age; Aging; Anatomy; Apoptosis; Apoptotic; Automobile Driving; Award; Binding; Biochemical; Biochemistry; Biological Assay; Biological Sciences; Brain; Brain Diseases; Caenorhabditis elegans; California; Cell Culture Techniques; Cell Death; Cell Line; Cell Survival; Cells; Cellular Stress; Cellular biology; Clinical; Data; Development; Disease; Doctor of Philosophy; Dopamine; Doxycycline; Elderly; Employee Strikes; Endoplasmic Reticulum; Environment; Evaluation; Fellowship; Financial cost; Foundations; Freezing; Genes; Genetic; Genetic Techniques; Goals; Grant; Guanosine Triphosphate Phosphohydrolases; Head; Health; Holly; Human; Hyperactive behavior; Idiopathic Parkinson Disease; Immunohistochemistry; In Vitro; Inherited; Institutes; Instruction; Knowledge; LRRK2 gene; Laboratories; Lead; Leadership; Mass Spectrum Analysis; Mediating; Medical; Medical Genetics; Medicine; Mentors; Mentorship; Michigan; Mission; Modeling; Molecular; Molecular Conformation; Morbidity - disease rate; Mutation; Nature; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neuroendocrine Cell; Neuroglia; Neurons; Neurosciences; Organism; Output; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Phosphotransferases; Physicians; Point Mutation; Postdoctoral Fellow; Process; Property; Protein Binding Domain; Proteins; Proteomics; Publishing; Research; Research Personnel; Residencies; Resources; Ribonucleases; Role; Running; San Francisco; Science; Scientist; Senior Scientist; Signal Transduction; Structure; Students; Substantia nigra structure; System; Techniques; Testing; Therapeutic; Toxic effect; Training; Training Programs; Transgenic Mice; Translating; United States National Institutes of Health; Universities; Variant; Washington; Work; aging brain; alpha synuclein; base; biological adaptation to stress; brain tissue; career; chemical genetics; design; disability; disorder control; distinguished professor; endoplasmic reticulum stress; experience; expression vector; genetic approach; human tissue; improved; in vivo; inhibitor/antagonist; instructor; medical schools; mid-career faculty; mortality; multidisciplinary; mutant; neuron loss; neuropathology; neurotoxicity; new therapeutic target; notch protein; novel; novel therapeutics; overexpression; post-doctoral training; professor; programs; protein folding; protein misfolding; relating to nervous system; research and development; response; skills; symposium; targeted treatment; tenure track

DESCRIPTION (provided by applicant): This is an application for the Paul B. Beeson Clinical Scientist Development Award in Aging (K08) for Dr. Annie Hiniker, a Clinical Instructor in Neuropathology at the University of California, San Francisco. The proposal describes a 5-year training program (coursework, conferences, national presentations, and mentored research) for the development of an academic career in the field of neurodegenerative neuropathology, with a particular focus on Parkinson's Disease (PD). This award will provide the core support necessary to establish Dr. Hiniker as an independent researcher in PD and to achieve the following career goals over the five-year term of this award: 1) master techniques in advanced neuroscience, 2) become an expert in PD neuropathology, and 3) develop leadership and mentoring skills necessary to run a top-notch laboratory. To achieve these goals, Dr. Hiniker has developed a plan and assembled a multidisciplinary advisory team of neuroscientists and physician-scientists specializing in cell stress, the unfolded protein response, neurodegenerative neuropathology, and PD genetics and mechanisms. The Applicant: Dr. Hiniker has been studying neurodegenerative disease since her freshman year at Harvard. She graduated from the Medical Scientist Training Program (MSTP) at the University of Michigan Medical School with junior AOA and received the Rackham Distinguished Dissertation award for one of the best dissertations in any field. Her graduate work focused on basic mechanisms of protein folding and misfolding. In June, 2013 Dr. Hiniker graduated from a combined anatomic pathology/neuropathology residency and fellowship at UCSF where she trained in the Physician-Scientist-Pathway. During her residency/fellowship and first year of postdoctoral research, she established novel in vitro, cell culture, and human tissue systems to study the mechanisms of cell death in PD. Through the proposed training program, Dr. Hiniker will expand her scientific skills so as to become an independent investigator studying the neuropathology and basic mechanisms of PD with a career goal of discovering novel therapeutic targets. Mentorship Environment and Formal Instruction: Dr. Hiniker is currently a clinical instructor of neuropathology at UCSF; she is expected to be promoted to a tenure track Assistant Professor within three years; this is not contingent on receiving the award. The proposed training program draws on the combined resources of the Oakes and Nussbaum Laboratories, the UCSF Institutes of Neurodegenerative Disease and Quantitative Biosciences, and the UCSF Division of Neuropathology. Scott Oakes, MD, and Bob Nussbaum, MD, will mentor the candidate's scientific development. Dr. Oakes is Associate Professor of Pathology with Tenure and an expert in protein folding stress responses in the cell; he has exceptional mentorship experience as Head of Advising of the UCSF Biomedical Sciences Graduate Program and Lead PI on a T32 postdoctoral training grant. Dr. Nussbaum is Holly Smith Distinguished Professor in Science and Medicine, Chief of the Division of Medical Genetics, and the neuroscientist who discovered the a-synuclein gene. He has made major advances in the study of PD and his record of mentoring residents, postdocs, and students is outstanding. To enhance Dr. Hiniker's training, an advisory committee of highly-regarded senior scientists including Drs Oakes and Nussbaum will provide scientific and career advice. This advisory committee also includes a neuroscientist specializing in protein misfolding in neurodegenerative disease (Stanley Prusiner, MD, Director of the UCSF Institute of Neurodegenerative Disease); a neuropathologist (Marta Margeta, MD, PhD, Assistant Professor of Neuropathology); and a proteomics expert (Nevan Krogan, PhD, Director of the California Institute of Quantitative Biosciences at UCSF). Dr. Hiniker's knowledge will be supplemented by advanced classes and seminars at UCSF, Cold Spring Harbor, and by structured one-on-one instruction with Dr. Thomas Montine at the University of Washington. Research: PD is the second most common neurodegenerative disorder and a significant cause of morbidity, mortality, and financial cost. Dr. Hiniker's long-term goal is to identify the molecular mechanisms of cell death in PD in order to find novel pathways that can be translated into rational therapeutics for PD. The objective of this project is to dissect the role of the Lrrk2 kinase in PD cell death pathways using complementary targeted approaches and large scale screens in both cell culture and human brain tissue via the following specific aims: 1) Determine the impact of Lrrk2 kinase activity on the signaling of Ire1a--master regulator of the unfolded protein response; 2) Define interdependency between the Lrrk2 kinase and GTPase domains; and 3) Delineate the Lrrk2 kinase-dependent and -independent cellular interactome. This research uses cell biology and biochemistry as well as human tissue studies to answer important questions about PD. This project follows the mission of the NIH and more specifically of the Paul B. Beeson RFA to further research on neural processes in the aging brain.

描述（由申请人提供）：这是为加州大学旧金山分校神经病理学临床讲师 Annie Hiniker 博士申请的 Paul B. Beeson 衰老临床科学家发展奖 (K08)。该提案描述了一个为期 5 年的培训计划（课程、会议、全国演讲和指导研究），用于发展神经退行性神经病理学领域的学术职业，特别关注帕金森病 (PD)。该奖项将为 Hiniker 博士成为 PD 独立研究员提供必要的核心支持，并在该奖项的五年期限内实现以下职业目标：1) 掌握先进神经科学技术，2) 成为以下领域的专家： PD 神经病理学，3) 培养运营一流实验室所需的领导和指导技能。为了实现这些目标，Hiniker 博士制定了一项计划，并组建了一个由神经科学家和医师科学家组成的多学科咨询团队，专门研究细胞应激、未折叠蛋白反应、神经退行性神经病理学以及 PD 遗传学和机制。申请人：希尼克博士从哈佛大学一年级起就开始研究神经退行性疾病。她以初级 AOA 毕业于密歇根大学医学院的医学科学家培训计划 (MSTP)，并获得了拉克姆杰出论文奖，该论文是所有领域中最好的论文之一。她的研究生工作重点是蛋白质折叠和错误折叠的基本机制。 2013 年 6 月，Hiniker 博士从加州大学旧金山分校的解剖病理学/神经病理学联合住院医师实习和研究员毕业，在那里她接受了医师-科学家途径的培训。在住院医师/研究员和博士后研究的第一年，她建立了新颖的体外、细胞培养和人体组织系统来研究帕金森病细胞死亡的机制。通过拟议的培训计划，Hiniker 博士将扩展她的科学技能，成为一名研究 PD 神经病理学和基本机制的独立研究者，其职业目标是发现新的治疗靶点。指导环境和正式指导：Hiniker 博士目前是 UCSF 神经病理学临床讲师；她预计将在三年内晋升为终身教授助理教授；这并不取决于是否获奖。拟议的培训计划利用了奥克斯和努斯鲍姆实验室、加州大学旧金山分校神经退行性疾病和定量生物科学研究所以及加州大学旧金山分校神经病理学部门的综合资源。医学博士斯科特·奥克斯 (Scott Oakes) 和医学博士鲍勃·努斯鲍姆 (Bob Nussbaum) 将指导候选人的科学发展。 Oakes 博士是终身教授病理学副教授，也是细胞中蛋白质折叠应激反应方面的专家。作为 UCSF 生物医学科学研究生项目的咨询主管和 T32 博士后培训补助金的首席 PI，他拥有卓越的指导经验。 Nussbaum 博士是 Holly Smith 科学与医学杰出教授、医学遗传学系主任，也是发现 α-突触核蛋白基因的神经科学家。他在 PD 研究方面取得了重大进展，并且在指导住院医生、博士后和学生方面的记录非常出色。为了加强希尼克博士的培训，由奥克斯博士和努斯鲍姆博士等备受尊敬的资深科学家组成的咨询委员会将提供科学和职业建议。该咨询委员会还包括一位专门研究神经退行性疾病中蛋白质错误折叠的神经科学家（Stanley Prusiner，医学博士，加州大学旧金山分校神经退行性疾病研究所所长）；神经病理学家（Marta Margeta，医学博士，博士，神经病理学助理教授）；以及蛋白质组学专家（Nevan Krogan 博士，加州大学旧金山分校加州定量生物科学研究所所长）。 Hiniker 博士的知识将通过加州大学旧金山分校冷泉港分校的高级课程和研讨会以及华盛顿大学 Thomas Montine 博士的结构化一对一指导得到补充。研究：PD 是第二常见的神经退行性疾病，也是发病率、死亡率和经济成本的重要原因。 Hiniker 博士的长期目标是确定 PD 细胞死亡的分子机制，以便找到可转化为合理的 PD 治疗方法的新途径。该项目的目标是 通过以下具体目标，使用互补的靶向方法和大规模筛选细胞培养物和人脑组织来剖析 Lrrk2 激酶在 PD 细胞死亡途径中的作用：1) 确定 Lrrk2 激酶活性对 Ire1a- 信号传导的影响-未折叠蛋白反应的主调节器； 2) 定义Lrrk2激酶和GTPase结构域之间的相互依赖性； 3) 描述 Lrrk2 激酶依赖和独立的细胞相互作用组。这项研究利用细胞生物学和生物化学以及人体组织研究来回答有关帕金森病的重要问题。该项目遵循 NIH，更具体地说是 Paul B. Beeson RFA 的使命，进一步研究衰老大脑的神经过程。