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

基本信息

批准号：
10481840
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
项目类别：
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/10481840
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

项目摘要

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.

项目摘要该提案描述了一个五年的职业发展计划线粒体代谢。首席研究员（PI）已完成神经化学的研究生培训以及UT西南部儿科神经病学的居住培训。他在研究方面有很强的背景神经代谢，在洛克菲勒大学的K08奖中，他的目标是扩大他的高级显微镜，转录组学和代谢组学的技能研究线粒体有缺陷代谢损害大脑发育并引起疾病。线粒体疾病最多代谢的先天错误的常见形式（1：3000出生）。这些疾病经常破坏发展大脑，特别是小脑的大脑，在约70％的患者中受到影响。小脑表型是特别是丙酮酸脱氢酶缺乏症（PDHD），这是最常见的线粒体之一儿童疾病，从临床上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理解已阻止治疗选择，目前仅限于有症状治疗。该项目的总体目标是确定基于小脑发育疾病的机制，并应用相应的有效疗法。为了实现这一目标，PI将调查发展和代谢与小脑的原型线粒体疾病中涉及异常小脑形成的机制参与：PDHD。 PI将通过与他的主要顾问博士的定制教程互动进行指导。玛丽·E·哈滕（Mary E. 贾斯汀·克罗斯（Ansabolomics）和托马斯·卡罗尔（Thomas Carroll）博士（生物信息学）。来自鼠标模型的初步数据 PDHD揭示小脑中的葡萄糖代谢受损，并且扩散和迁移颗粒细胞（GC）受到损害。中心假设是PDHD通过限制破坏小脑组 GC的发育由于葡萄糖代谢受损而导致。提出了两个具体目标：1）阐明 PDHD中小脑形成异常的发展过程； 2）确定代谢在这种情况下，与小脑疾病有关的机制。在第一个目标下，GC开发的关键步骤将使用高级显微镜研究。为了第二个目标，经过验证的转录组学和代谢组学将应用于识别和治疗PDHD小脑中的代谢缺陷。提出的研究很重要因为期望它可以提高我们对线粒体疾病如何破坏小脑的理解开发和转化有希望的发现给患者。该建议具有创新性，因为它结合了发育神经生物学和生物化学的高级方法论先前解决无法回答的问题。长期，PI旨在运用学会的技能来扩大对为了改善患者护理而损害小脑发育的线粒体疾病。