Role of Elevated Diet-linked TOR Activity and Protein Synthesis in Parkinson's Disease Neurodegeneration

饮食相关的 TOR 活性和蛋白质合成升高在帕金森病神经变性中的作用

• 批准号: 8948116
• 负责人: Ian Martin
• 金额: $ 13.05万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8948116
• 关键词: Address; Adult; Affect; Affinity Chromatography; Aging; Aging-Related Process; Amino Acids; Animal Model; Attenuated; Automobile Driving; Bioinformatics; Biology of Aging; Cells; Cessation of life; Chemicals; Consumption; Data; Diet; Disease; Disease model; Drosophila genus; Etiology; Functional disorder; Gene Expression; General Population; Genetic; Genetic Translation; Goals; Grant; Homeostasis; Human; In Vitro; Individual; Intake; International; Knowledge; Lead; Life; Link; Longevity; Mediating; Mentors; Metabolic; Molecular; Mutation; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Nutrient; Organism; Parkinson Disease; Pathway interactions; Phenotype; Play; Population; Prevalence; Process; Protein Biosynthesis; Proteins; Public Health; Publishing; Relative (related person); Reporter; Research; Research Methodology; Research Personnel; Research Training; Ribosomes; Risk; Risk Factors; Role; Series; Signal Transduction; Sirolimus; Structure; Therapeutic Intervention; Training; Training Programs; Transgenic Organisms; Translating; Translational Research; Translations; Universities; Untranslated Regions; Up-Regulation; Writing; age related; aged; career; deep sequencing; design; dietary excess; dietary restriction; dopaminergic neuron; fly; genome-wide; leucine-rich repeat kinase 2; meetings; motor disorder; neuron loss; novel; post-doctoral training; prevent; protective effect; public health relevance; research study; therapeutic target

 DESCRIPTION (provided by applicant): I am a young neuroscientist with doctoral training in the biology of aging and post-doctoral training in molecular neurodegeneration research from Johns Hopkins University. My long-term career goal is to become an independent investigator focusing on mechanisms of neurodegeneration in Parkinson's disease (PD) related to the aging process and mRNA translation. My goal over the next five years is to acquire additional knowledge and expertise in translation research and methodology in order to probe the role of altered mRNA translation in PD neurodegeneration. To attain these goals, I have assembled a team of outstanding mentors, and together we have developed a structured training program that includes substantial hands-on research training in translational profiling experiments and bioinformatics analysis of deep sequencing data as well as participation in lab presentations, departmental seminars, formal courses, international scientific meetings, and grant writing training. The prevalence of PD, which affects approximately 1% of the population over 60, is projected to double by 2040 with increased human longevity. As aging is a clear risk factor for developing PD, mechanisms driving the aging process might be important in the progressive degeneration of dopamine neurons underlying motor dysfunction in PD. We discovered that mutations in LRRK2 (leucine-rich repeat kinase 2) cause PD- related phenotypes in human neurons and Drosophila by increasing bulk mRNA translation. Compelling evidence from dietary restriction studies suggests that life span and other aging parameters are affected by the activity of TOR (target of rapamycin), which regulates organismal homeostasis in part through governing mRNA translation. A key unresolved question is whether the metabolic influence on mRNA translation through TOR signaling can drive dopamine neuron degeneration in aging organisms. My mentors and I have designed a series of studies to address this question and to also identify critical translational targets and mechanistic pathways linking excess mRNA translation through diet or G2019S LRRK2 expression to dopamine neuron degeneration. The research aims of the Application are to (i) determine if excess dietary amino acid consumption causes age-related dopamine neuron degeneration and locomotor dysfunction through elevated TOR activity (ii) determine if reduced amino acid consumption blocks these phenotypes in aged G2019S LRRK2 transgenic flies through attenuating TOR activity (iii) determine the effects of excess amino acid consumption and G2019S LRRK2 on the mRNA translation profile of vulnerable dopamine neurons relative to other neurons (iv) delineate the role of G2019S LRRK2 and diet-linked TOR translational targets in neurodegeneration. The use of Drosophila in these studies will allow for rapid and high throughput disease modeling in an organism that recapitulates the age-related loss of dopamine neurons and locomotor dysfunction caused by PD-linked mutations. Collectively, these studies will probe the intersection of mRNA translation, aging and neurodegenerative disease and lead to the identification of potential therapeutic targets.

 描述（由申请人提供）：我是一位年轻的神经科学家，在约翰·霍普金斯大学接受过衰老生物学博士培训和分子神经变性研究博士后培训，我的长期职业目标是成为一名专注于衰老机制的独立研究者。帕金森病 (PD) 中的神经变性与衰老过程和 mRNA 翻译相关。我未来五年的目标是获得翻译研究和方法方面的更多知识和专业知识，以探讨 mRNA 翻译在 PD 神经变性中的作用。为了实现这些目标，我组建了一支由优秀导师组成的团队，我们共同开发了一个结构化的培训计划，其中包括翻译分析实验和深度测序数据的生物信息学分析方面的大量实践研究培训以及参与实验室演示，部门研讨会、正式课程、国际科学会议和资助写作培训 帕金森病的患病率预计到 2040 年将增加一倍，因为老龄化是一个明显的风险因素，该病影响 60 岁以上的人口。在 PD 的发展过程中，驱动衰老过程的机制可能在 PD 运动功能障碍的多巴胺神经元进行性退化中发挥重要作用。我们发现 LRRK2（富含亮氨酸重复激酶 2）的突变通过增加人类神经元和果蝇中的 PD 相关表型。来自饮食限制研究的令人信服的证据表明，寿命和其他衰老参数受到活动的影响。 TOR（雷帕霉素的靶点），部分通过控制 mRNA 翻译来调节生物体内平衡，一个未解决的关键问题是，通过 TOR 信号传导对 mRNA 翻译的代谢影响是否会导致衰老生物体中的多巴胺神经元退化。我们进行了一系列研究来解决这个问题，并确定通过饮食或 G2019S LRRK2 表达导致的过量 mRNA 翻译与多巴胺神经元变性之间的关键翻译靶点和机制途径。该申请的研究目的是 (i) 确定过量膳食氨基酸消耗是否会通过 TOR 活性升高导致与年龄相关的多巴胺神经元变性和运动功能障碍 (ii) 确定减少氨基酸消耗是否会通过以下方式阻止老年 G2019S LRRK2 转基因果蝇的这些表型减弱 TOR 活性 (iii) 确定过量氨基酸消耗和 G2019S LRRK2 对脆弱多巴胺神经元相对于其他神经元的 mRNA 翻译谱的影响 (iv) 描绘G2019S LRRK2 和饮食相关 TOR 翻译靶点在神经退行性变中的作用在这些研究中使用果蝇将允许在生物体中进行快速、高通量的疾病建模，重现与年龄相关的多巴胺神经元损失和 PD 引起的运动功能障碍。总的来说，这些研究将探讨 mRNA 翻译、衰老和神经退行性疾病的交叉点，并确定潜在的治疗靶点。