Mechanisms and therapies for cerebellar development under defective mitochondrial metabolism

项目摘要 这份提案描述了一项为期五年的先天缺陷神经生物学职业发展计划。 线粒体代谢。首席研究员(PI)已完成神经化学研究生培训 以及德克萨斯大学西南分校的儿科神经学住院医师培训。他在研究…方面有很强的背景 神经代谢，在洛克菲勒大学获得K08奖的过程中，他的目标是扩大他的 掌握高级显微镜、转录组学和代谢组学方面的技能，研究线粒体缺陷 新陈代谢影响大脑发育并导致疾病。线粒体疾病是最常见的 常见的先天代谢性疾病(1：3000)。这些紊乱经常扰乱发育。 大脑，特别是小脑，约70%的患者会受到影响。小脑的表型是 尤其是在丙酮酸脱氢酶缺乏症(PDHD)中，这是最常见的线粒体之一 儿童疾病，临床表现从严重的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性理解阻止了 治疗选择，目前仅限于对症治疗。这个项目的总体目标是 是确定线粒体疾病中小脑发育疾病的基础机制，并应用 相应有效的治疗方法。为了实现这一目标，PI将调查发育和新陈代谢 典型小脑线粒体病小脑异常形成机制的研究 参与：多发性硬化症。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)、 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，细胞的增殖和迁移 颗粒细胞(GC)受损。中心假说是，PDHD通过限制小脑的形成 由于糖代谢受损而导致的GC的发展。提出了两个具体的目的：1)阐明 PDHD患者小脑异常形成的发育过程；2)确定代谢 在这种情况下，与小脑疾病相关的机制。在第一个目标下，GC发展的关键步骤 将使用先进的显微镜进行研究。对于第二个目标，已证实的转录组学和代谢组学将 用于识别和治疗PDHD小脑的代谢缺陷。本文提出的研究具有重要意义。 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翻译给患者。这项建议具有创新性，因为它结合了 来自发育神经生物学和生物化学的高级方法 无法回答的问题。从长远来看，PI的目标是应用所学的技能来扩大对 为了改善病人护理而影响小脑发育的线粒体紊乱。

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.