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

 描述（由申请人提供）：我是一名年轻的神经科学家，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独立的研究者，专注于帕金森病（PD）中与衰老过程和mRNA翻译相关的神经退行性变机制。在接下来的五年里，我的目标是获得翻译研究和方法学方面的额外知识和专业知识，以探索改变mRNA翻译在PD神经变性中的作用。为了实现这些目标，我组建了一个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，以及参加实验室演示，部门研讨会，正式课程，国际科学会议和赠款写作培训。PD的患病率影响约1%的60岁以上人口，预计到2040年将翻一番，人类寿命延长。由于衰老是发展PD的明显风险因素，因此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变性中很重要。我们发现LRRK2（富含亮氨酸的重复序列激酶2）的突变通过增加大量mRNA翻译在人类神经元和果蝇中引起PD相关表型。来自饮食限制研究的有力证据表明，活动会影响寿命和其他衰老参数 TOR（雷帕霉素的靶标），其部分通过控制mRNA翻译来调节生物体内平衡。一个关键的未解决的问题是，通过TOR信号传导对mRNA翻译的代谢影响是否可以驱动衰老生物体中的多巴胺神经元变性。我和我的导师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将过量mRNA翻译通过饮食或G2019 S LRRK 2表达与多巴胺神经元变性联系起来的机制途径。本申请的研究目的是（i）确定过量的膳食氨基酸消耗是否通过升高的TOR活性引起年龄相关的多巴胺神经元变性和运动功能障碍（ii）确定减少的氨基酸消耗是否通过减弱TOR活性阻断老年G2019S LRRK2转基因果蝇中的这些表型（iii）确定过量氨基酸消耗和G2019S LRRK2对相对于其他神经元的易损多巴胺神经元的mRNA翻译谱的影响（iv）描绘G2019S LRRK2和饮食相关的TOR翻译靶标在神经变性中的作用。在这些研究中使用果蝇将允许在生物体中进行快速和高通量的疾病建模，该生物体重现了由PD连锁突变引起的与年龄相关的多巴胺神经元损失和运动功能障碍。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叉点，并识别潜在的治疗靶点。

 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.