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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

基本信息

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
项目类别：
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

项目摘要

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）：这是保罗B的应用程序。Beeson老龄化临床科学家发展奖（K 08）授予加州大学旧金山分校弗朗西斯科神经病理学临床讲师Annie Hiniker博士。该提案描述了一个为期5年的培训计划（课程，会议，国家演示和指导研究），用于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）。该奖项将提供必要的核心支持，以建立希尼克博士作为PD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）掌握先进神经科学技术，2）成为PD神经病理学专家，3）发展领导和指导技能，以运行一流的实验室。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学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开始就一直在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），获得了初级AOA，并因其在任何领域的最佳论文之一而获得了拉克姆杰出论文奖。她的研究生工作主要集中在蛋白质折叠和错误折叠的基本机制。2013年6月，Hiniker博士毕业于UCSF的解剖病理学/神经病理学住院医师和奖学金，在那里她接受了医生-科学家-途径的培训。在她的居住/奖学金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，以研究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。导师环境和正式教学：希尼克博士目前是加州大学旧金山分校神经病理学的临床讲师;她预计将在三年内晋升为终身助理教授;这并不取决于获得该奖项。拟议的培训计划借鉴了奥克斯和努斯鲍姆实验室，UCSF神经退行性疾病和定量生物科学研究所，以及UCSF神经病理学部门的综合资源。医学博士斯科特奥克斯和医学博士鲍勃努斯鲍姆将指导候选人的科学发展。奥克斯是终身病理学副教授和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博士后培训补助金的首席PI拥有出色的指导经验。Nussbaum博士是冬青史密斯科学和医学杰出教授，医学遗传学系主任，发现了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，他指导住院医师，博士后和学生的记录非常出色。为了加强希尼克博士的培训，一个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名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，UCSF神经退行性疾病研究所所长）;一名神经病理学家（玛尔塔Margeta，医学博士，哲学博士，神经病理学助理教授）;和一名蛋白质组学专家（Nevan Krogan，哲学博士，UCSF加州定量生物科学研究所所长）。希尼克博士的知识将通过在加州大学旧金山分校冷泉港的高级课程和研讨会以及在华盛顿大学与托马斯·蒙蒂博士进行的结构化一对一教学来补充。研究：PD是第二种最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，以找到可以转化为PD合理疗法的新途径。本项目的目标是使用互补靶向方法和在细胞培养物和人脑组织中的大规模筛选来剖析Lrrk 2激酶在PD细胞死亡途径中的作用，通过以下具体目的：1）确定Lrrk 2激酶活性对Ire 1a信号传导的影响-Ire 1a是未折叠蛋白应答的主要调节剂; 2）确定Lrrk 2激酶和GT3结构域之间的相互依赖性;和3）描绘Lrrk 2激酶依赖性和非依赖性细胞相互作用组。这项研究使用细胞生物学和生物化学以及人体组织研究来回答有关PD的重要问题。该项目遵循NIH的使命，更具体地说是Paul B。Beeson RFA旨在进一步研究衰老大脑中的神经过程。