Mechanisms and therapies for cerebellar development under defective mitochondrial metabolism

项目摘要 这项建议描述了一个为期五年的职业发展计划，在神经生物学的先天性错误， 线粒体代谢主要研究者（PI）已完成神经化学研究生培训 以及德州大学西南分校的儿科神经学住院医师培训他有很强的研究背景， 神经代谢，并在洛克菲勒大学的K 08奖的过程中，他的目标是扩大他的 先进的显微镜，转录组学和代谢组学的技能，研究缺陷的线粒体如何 新陈代谢损害大脑发育并导致疾病。线粒体疾病是最常见的 一种常见的先天性代谢缺陷（1：3000出生）。这些疾病经常会破坏 大脑，特别是小脑，约70%的患者受到影响。小脑表型是 丙酮酸脱氢酶缺乏症（PDHD）尤其明显，PDHD是最常见的线粒体 儿童疾病，临床表现为从严重小脑发育不全到间歇性共济失调。缺乏 对线粒体疾病中小脑缺陷的机械理解阻止了 治疗选择，目前仅限于对症治疗。本项目的总体目标 是确定线粒体疾病中小脑发育疾病的潜在机制， 有效的治疗方法。为了实现这一目标，PI将研究发育和代谢 小脑线粒体病的典型模型中小脑形成异常的机制 参与：PDHD。PI将通过与他的主要顾问Dr. 玛丽E.哈滕（神经发育）和三位共同导师，纳撒尼尔海因茨博士（分子神经生物学），博士。 贾斯汀·克罗斯（代谢组学）和托马斯卡罗尔博士（生物信息学）。来自小鼠模型的初步数据 PDHD显示小脑葡萄糖代谢受损， 颗粒细胞（GC）受损。核心假设是PDHD通过限制小脑的形成， 由于葡萄糖代谢受损而发生GC。提出了两个具体目标：1）阐明 PDHD中异常小脑形成的基础的发育过程;和2）识别代谢 在这种情况下与小脑疾病相关的机制。在第一个目标下，GC开发的关键步骤 将使用先进的显微镜进行研究。对于第二个目标，经过验证的转录组学和代谢组学将 用于识别和治疗PDHD小脑中的代谢缺陷。所提出的研究是有意义的 因为它有望促进我们对线粒体疾病如何破坏小脑的理解， 开发并将有希望的发现转化为患者。这项建议是创新的，因为它结合了 从发展神经生物学和生物化学的先进方法来解决以前 无法回答的问题从长远来看，PI的目标是应用所学的技能，以扩大对 线粒体疾病，损害小脑发育，以改善病人的护理。

Project Summary This proposal describes a five-year career development program in the neurobiology of inborn errors of mitochondrial metabolism. The principal investigator (PI) has completed postgraduate training in neurochemistry and residency training in pediatric neurology at UT Southwestern. He has a strong background in the study of neurometabolism and, over the course of this K08 award at The Rockefeller University, he aims to expand his skills in advanced microscopy, transcriptomics, and metabolomics to study how defective mitochondrial metabolism compromises brain development and causes disease. Mitochondrial disorders represent the most common form of inborn errors of metabolism (1:3000 births). These disorders frequently disrupt the development of the brain, particularly of the cerebellum, which is affected in ~70% of patients. The cerebellar phenotype is especially pronounced in pyruvate dehydrogenase deficiency (PDHD), one of the most common mitochondrial disorders in children, presenting clinically from severe cerebellar hypoplasia to intermittent ataxia. The lack of mechanistic understanding of cerebellar deficits in mitochondrial diseases has prevented the expansion of therapeutic options, which are currently limited to symptomatic treatments. The overall objective of this project is to identify mechanisms that underlie cerebellar developmental disease in mitochondrial disorders and apply effective therapies accordingly. To achieve this goal, the PI will investigate developmental and metabolic mechanisms involved in abnormal cerebellar formation in the prototypical mitochondrial disease with cerebellar involvement: PDHD. The PI will be mentored via customized tutorial interactions with his primary advisor, Dr. Mary E. Hatten (neurodevelopment), and three co-mentors, Dr. Nathaniel Heintz (molecular neurobiology), Dr. Justin Cross (metabolomics), and Dr. Thomas Carroll (bioinformatics). Preliminary data from a mouse model of PDHD reveal that glucose metabolism in the cerebellum is impaired and that proliferation and migration of granule cells (GC) is compromised. The central hypothesis is that PDHD disrupts cerebellar formation by limiting GC development as a result of impaired glucose metabolism. Two specific aims are proposed: 1) to elucidate developmental processes that underlie abnormal cerebellar formation in PDHD; and 2) to identify metabolic mechanisms relevant to the cerebellar disease in this condition. Under the first aim, key steps of GC development will be studied using advanced microscopy. For the second aim, proven transcriptomics and metabolomics will be applied to identify and treat metabolic defects in the PDHD cerebellum. The research proposed is significant because it is expected to advance our understanding of how mitochondrial diseases disrupt cerebellar development and translate promising findings to patients. This proposal is innovative because it combines advanced methodologies from developmental neurobiology and biochemistry to address previously unanswerable questions. Long-term, the PI aims to apply the skills learned to expand the understanding of mitochondrial disorders that compromise cerebellar development in order to improve patient care.