Mechanisms and therapies for cerebellar development under defective mitochondrial metabolism

线粒体代谢缺陷下小脑发育的机制和治疗

• 批准号: 10231085
• 负责人: Isaac Marin-Valencia
• 金额: $ 19.53万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231085
• 关键词: Address; Affect; Affinity Chromatography; Ataxia; Award; Bioinformatics; Birth; Brain; Carbon; Cells; Cerebellar Diseases; Cerebellum; Child; Childhood; Citric Acid Cycle; Clinical; Congenital cerebellar hypoplasia; Consumption; Custom; Data; Defect; Development; Developmental Biochemistry; Developmental Process; Disease; Energy Metabolism; Fatty Acids; Fiber; Future; Gene Expression; Goals; Growth; Hereditary Disease; Human; Imaging technology; Impairment; Inborn Errors of Metabolism; Internal Granular Layer; K-Series Research Career Programs; Knock-out; Knowledge; Life; LoxP-flanked allele; Mentors; Metabolic; Metabolic Pathway; Metabolism; Methodology; Methods; Microscopy; Mission; Mitochondria; Mitochondrial Diseases; Mitotic; Molecular Neurobiology; Neurobiology; Neuroglia; Neurologic; Neurologic Dysfunctions; Neurologic Symptoms; Neurons; Outcome; Pathway Analysis; Pathway interactions; Patient Care; Patients; Pediatric Neurology; Pharmacology; Phenotype; Play; Positioning Attribute; Principal Investigator; Process; Program Development; Public Health; Research; Residencies; Ribosomes; Role; Testing; Therapeutic; Time; Training; Translating; Triglycerides; United States National Institutes of Health; Universities; associated symptom; base; career development; cell type; conditional knockout; design; developmental disease; developmental neurobiology; disability; effective therapy; glucose metabolism; granule cell; human disease; impaired brain development; improved; innovation; ketogenic diet; metabolomics; migration; mitochondrial metabolism; mouse model; neurochemistry; neurodevelopment; novel therapeutics; palliative; prevent; programs; pyruvate dehydrogenase; skills; symptom treatment; therapeutic target; transcriptomics

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.

项目概要 该提案描述了先天性缺陷神经生物学领域的五年职业发展计划 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 UT 西南医学中心儿科神经学住院医师培训。他有深厚的研究背景 神经代谢，在洛克菲勒大学获得 K08 奖项的过程中，他的目标是扩大他的研究范围 先进的显微镜、转录组学和代谢组学技能，用于研究线粒体缺陷如何 新陈代谢会损害大脑发育并导致疾病。线粒体疾病是最常见的 先天性代谢缺陷的常见形式（1:3000 出生）。这些疾病经常扰乱发育 大脑，尤其是小脑，约 70% 的患者受到影响。小脑的表型是 在丙酮酸脱氢酶缺乏症（PDHD）中尤其明显，这是最常见的线粒体疾病之一 儿童疾病，临床表现为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制理解阻止了线粒体疾病的扩大 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机制并应用 采取相应的有效疗法。为了实现这一目标，PI 将研究发育和代谢 典型线粒体疾病小脑异常小脑形成的机制 参与：PDHD。 PI 将通过与其主要顾问 Dr. 的定制教程互动进行指导。 Mary E. Hatten（神经发育）和三位共同导师 Nathaniel Heintz 博士（分子神经生物学）、Dr. Justin Cross（代谢组学）和 Thomas Carroll 博士（生物信息学）。小鼠模型的初步数据 PDHD 揭示小脑中的葡萄糖代谢受损，并且小脑的增殖和迁移 颗粒细胞 (GC) 受到损害。中心假设是 PDHD 通过限制小脑的形成来破坏小脑的形成。 糖代谢受损导致GC的发生。提出了两个具体目标：1）阐明 PDHD 中小脑形成异常的发育过程； 2) 识别代谢 与这种情况下的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 可用于识别和治疗 PDHD 小脑的代谢缺陷。所提出的研究意义重大 因为它有望增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给患者。该提案具有创新性，因为它结合了 发育神经生物学和生物化学的先进方法可以解决以前的问题 无法回答的问题。从长远来看，PI 的目标是运用所学到的技能来扩大对 损害小脑发育的线粒体疾病，以改善患者护理。