Neuronal Mechanisms of Metabolic and Genetic Defects of the Peroxisome

过氧化物酶体代谢和遗传缺陷的神经机制

基本信息

批准号：
10547818
负责人：
Michael Francis Wangler
金额：
$ 47.38万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10547818
关键词：
Address Adult Aging Alzheimer&apos s Disease Anabolism Animal Model Bile Acid Biosynthesis Pathway Bile Acids Biochemical Biochemical Pathway Biogenesis Biological Markers Biological Process Biology Blood Tests Catabolism Characteristics Clinical Research Code Data Dedications Defect Development Diagnosis Diagnostic Disease Drosophila genus Eukaryotic Cell Fatty Acids Functional disorder Genes Genetic Genetic Diseases Genetic Screening Genomics Health Human Impairment Individual Learning Length Lipids Longevity Mediating Medical Membrane Metabolic Metabolism Methods Microgyria Molecular Probes Mutation Nervous System Nervous System Physiology Neurologic Neurons Obesity Organelles Patients Pattern Peroxisomal Disorders Phenotype Phospholipids Physicians Plasmalogens Point Mutation Production Proteins Quality of life Rare Diseases Reactive Oxygen Species Research Research Personnel Retinal Degeneration Role Science Scientist Seizures Series Side Sphingolipids Sphingomyelins Study models System Technology Testing Therapeutic Effect Variant Very Long Chain Fatty Acid X Chromosome autosome branched chain fatty acid career de novo mutation effective therapy experimental study fly genetic manipulation genetic technology genome sequencing hearing impairment human disease human subject improved in vivo innovation insight knock-down leukodystrophy loss of function metabolome metabolomics model organism mouse model mutant nervous system disorder neurodegenerative phenotype novel peroxisome pharmacologic rare genetic disorder research study therapeutic target tool translational impact

项目摘要

PROJECT SUMMARY Peroxisomes are fundamental sub-cellular organelles present in all eukaryotic cells. Peroxisomes participate in a number of biochemical pathways including catabolism of very-long-chain fatty acids, branched chain fatty acids, and bile acids, the biosynthesis of plasmalogen lipids, and mediate a number of crucial biological processes. Human diseases due to lack of peroxisomes are severe multisystem diseases These conditions, called peroxisome biogenesis disorders, Zellweger-spectrum disorders (PBD-ZSD) illustrate how peroxisomes are required for human health. Insights from studies in PBD-ZSD have been applied to common disease such as Alzheimer’s disease. In order to probe the molecular mechanisms that underlie PBD-ZSD I use genomics, untargeted metabolomics and genetic technology in Drosophila. I am a dedicated physician-scientist devoting my career to the study of PBD-ZSD, having made several contributions. First, I have used metabolomics to define a pattern of biochemical abnormalities or a “PBD-ZSD Metabolome” a characteristic signature of these diseases that interestingly includes reduced sphingomyelins, a previously unrecognized biomarker of PBD-ZSD. Second, my lab has used innovative genetic technology in Drosophila to further probe consequences of peroxisomal biology for neurons. For example, in a large forward genetic screen on the Drosophila X- chromosome we identified novel genes that alter peroxisomes in vivo and we have shown these are candidate neurological disease genes. Finally, using genomics I have developed a track record of diagnosing undiagnosed individuals who have novel or unique mutations in genes such as ACOX1, DNM1L, PEX1 and PEX16, and these studies point to novel genetic mechanisms for peroxisomal disease. Based on my studies of sphingomyelin I hypothesize that peroxisomal dysfunction leads to altered composition of the side-chains of sphingomyelins resulting in impaired neurological function in PBD-ZSD. I also propose, based on animal model studies that peroxisomes are required both during development and during aging for nervous system function. Finally, my preliminary data suggests that de novo mutations can impact peroxisomal genes, which are traditionally considered “autosomal recessive” and can be an important mechanism for peroxisomal disease. In this proposal we use clinical studies, unique model organism technology and genomic and metabolomic technology to test these hypotheses and advance studies of PBD- ZSD towards better diagnosis, treatment and improved quality of life for patients.

项目概要过氧化物酶体是所有真核细胞中存在的基本亚细胞细胞器。参与许多生化途径，包括极长链脂肪的分解代谢酸、支链脂肪酸和胆汁酸，缩醛磷脂脂质的生物合成，以及由于缺乏过氧化物酶体，介导了许多重要的人类疾病。是严重的多系统疾病这些病症称为过氧化物酶体生物发生障碍，齐薇格谱疾病 (PBD-ZSD) 说明了人类如何需要过氧化物酶体 PBD-ZSD 研究的见解已应用于常见疾病，例如为了探究 PBD-ZSD 的分子机制，我使用了这种方法。我专注于果蝇基因组学、非靶向代谢组学和遗传技术。医生科学家将我的职业生涯奉献给 PBD-ZSD 的研究，取得了多项成果首先，我使用代谢组学来定义生化异常或的模式。 “PBD-ZSD 代谢组”是这些疾病的特征特征，有趣的是包括其次，我的实验室发现了减少的鞘磷脂，这是一种以前未被识别的 PBD-ZSD 生物标志物。在果蝇中使用创新的遗传技术来进一步探讨过氧化物酶体的后果例如，在果蝇 X- 上进行大型正向遗传筛选。我们在染色体上发现了改变体内过氧化物酶体的新基因，并且我们已经证明了这些基因最后，我利用基因组学开发了一条轨迹。诊断未确诊个体的记录，这些个体具有新颖或独特的基因突变，例如如 ACOX1、DNM1L、PEX1 和 PEX16，这些研究指出了新的遗传机制根据我对鞘磷脂的研究，我服用了过氧化物酶体疾病。功能障碍导致鞘磷脂侧链组成改变，从而导致根据动物模型研究，我还提出 PBD-ZSD 中神经功能受损。神经系统功能在发育和衰老过程中都需要过氧化物酶体。最后，我的初步数据表明从头突变可以影响过氧化物酶体基因，传统上被认为是“常染色体隐性遗传”，可能是一个重要的机制在本提案中，我们使用临床研究、独特的模型生物技术。以及基因组和代谢组学技术来检验这些假设并推进 PBD-的研究 ZSD 致力于更好的诊断、治疗并提高患者的生活质量。