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

• 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
• 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' 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

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。过氧化物酶体 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 介导许多重要的生物过程。缺乏过氧化物酶体导致人类疾病 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 健康。 PBD-ZSD 研究的见解已应用于常见疾病，例如 阿尔茨海默病。为了探究 PBD-ZSD 的分子机制，我使用 果蝇基因组学、非靶向代谢组学和遗传技术。我是一个奉献者 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 贡献。首先，我使用代谢组学来定义生化异常的模式或 “PBD-ZSD 代谢组”是这些疾病的特征特征，有趣的是包括 鞘磷脂减少，这是一种以前未被识别的 PBD-ZSD 生物标志物。其次，我的实验室有 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 神经元生物学。例如，在果蝇 X 的大型正向遗传筛选中 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 是候选神经系统疾病基因。最后，利用基因组学，我开发了一条轨道 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 过氧化物酶体疾病。根据我对鞘磷脂的研究，我假设过氧化物酶体 功能障碍导致鞘磷脂侧链组成改变，从而导致 PBD-ZSD 神经功能受损。我还建议，根据动物模型研究 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 过氧化物酶体疾病。在这个提案中，我们使用临床研究、独特的模式生物技术 以及基因组和代谢组学技术来检验这些假设并推进 PBD- ZSD 致力于更好的诊断、治疗并提高患者的生活质量。