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

 描述(申请人提供)：我是一名年轻的神经学家，曾在约翰·霍普金斯大学接受过衰老生物学方面的博士培训，并在分子神经变性研究方面接受过博士后培训。我的长期职业目标是成为一名独立的研究员，专注于帕金森病(PD)中与衰老过程和mRNA翻译相关的神经变性机制。我在未来五年的目标是在翻译研究和方法学方面获得更多的知识和专业知识，以探索改变的mRNA翻译在帕金森病神经变性中的作用。为了实现这些目标，我组建了一支优秀的导师团队，我们共同制定了一项结构化的培训计划，其中包括翻译图谱实验和深度测序数据的生物信息学分析方面的大量动手研究培训，以及参与实验室演示、部门研讨会、正式课程、国际科学会议和拨款撰写培训。帕金森病的患病率约占60岁以上人口的1%，预计到2040年，随着人类寿命的延长，帕金森病的患病率将翻一番。由于衰老是发展为帕金森病的一个明显的危险因素，在帕金森病患者运动功能障碍的多巴胺神经元的进行性变性过程中，驱动衰老过程的机制可能是重要的。我们发现，LRRK2(富含亮氨酸的重复蛋白激酶2)的突变通过增加大量的mRNA翻译而导致人类神经元和果蝇中与PD相关的表型。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运动的影响 TOR(雷帕霉素的靶标)，部分通过控制mRNA的翻译来调节组织的动态平衡。一个关键的悬而未决的问题是，通过TOR信号对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。我和我的导师们设计了一系列研究来解决这个问题，并确定关键的翻译靶点和机制途径，将通过饮食或G2019S LRRK2表达过量的mRNA翻译与多巴胺神经元退化联系起来。本应用程序的研究目的是(I)确定过量饮食氨基酸摄入是否通过提高TOR活性导致增龄相关的多巴胺神经元变性和运动功能障碍(Ii)确定氨基酸消耗减少是否通过降低TOR活性来阻止老年G2019S LRRK2转基因果蝇的这些表型(Iii)确定过量氨基酸摄入和G2019S LRRK2对易受伤害的多巴胺神经元相对于其他神经元的mRNA翻译谱的影响(Iv)阐明G2019S LRRK2和饮食相关的TOR翻译靶点在神经变性中的作用。在这些研究中使用果蝇将允许在一个有机体中快速和高通量地建立疾病模型，该模型概括了与年龄相关的多巴胺神经元的丢失和PD连锁突变导致的运动功能障碍。总的来说，这些研究将探索mRNA翻译、衰老和神经退行性疾病的交集，并导致确定潜在的治疗靶点。

 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.