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

描述（由申请人提供）：这是一份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Paul B. Beeson老年临床科学家发展奖（K08）的申请书。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），以发展神经退行性神经病理学领域的学术生涯，特别关注帕金森病（PD）。该奖项将为Hiniker博士提供必要的核心支持，使其成为PD领域的独立研究人员，并在该奖项的五年任期内实现以下职业目标：1)掌握高级神经科学技术，2)成为PD神经病理学专家，3)培养管理一流实验室所需的领导和指导技能。为了实现这些目标，Hiniker博士制定了一个计划，并组建了一个由神经科学家和医生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和PD遗传学和机制。Hiniker博士从哈佛大学一年级就开始研究神经退行性疾病。她毕业于密歇根大学医学院的医学科学家培训计划（MSTP），获得初级AOA，并获得拉克姆杰出论文奖，这是所有领域中最好的论文之一。她的研究生工作集中在蛋白质折叠和错误折叠的基本机制。2013年6月，Hiniker博士从UCSF的解剖病理学/神经病理学联合住院医师和奖学金毕业，在那里她接受了医生-科学家途径的培训。在她的住院医师/研究员和博士后研究的第一年，她建立了新的体外、细胞培养和人体组织系统来研究PD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，成为一名独立的研究者，研究PD的神经病理学和基本机制，并以发现新的治疗靶点为职业目标。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；她有望在三年内晋升为终身助理教授；这并不取决于是否获得该奖项。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Scott Oakes和医学博士Bob Nussbaum将指导候选人的科学发展。奥克斯博士是病理学终身副教授，也是细胞中蛋白质折叠应激反应的专家；他作为UCSF生物医学科学研究生项目的咨询负责人和T32博士后培训资助的领导PI，拥有出色的指导经验。努斯鲍姆博士是霍利史密斯科学和医学杰出教授，医学遗传学主任，以及发现a-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，他指导住院医师、博士后和学生的记录非常出色。为了加强Hiniker博士的培训，一个由包括Oakes博士和Nussbaum博士在内的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名神经科学家，专门研究神经退行性疾病中的蛋白质错误折叠（Stanley Prusiner， MD， UCSF神经退行性疾病研究所所长）；神经病理学家（Marta Margeta，医学博士，神经病理学助理教授）；和蛋白质组学专家（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的高级课程和研讨会，以及华盛顿大学Thomas Montine博士的一对一指导来补充。研究：帕金森病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中细胞死亡的分子机制，以便找到新的途径，可以转化为PD的合理治疗方法。这个项目的目标是

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.