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.

项目总结 过氧化物体是存在于所有真核细胞中的基本亚细胞器。过氧酶体 参与多种生化途径，包括超长链脂肪的分解代谢 酸、支链脂肪酸和胆汁酸，血浆原脂质的生物合成，以及 调节一些关键的生物过程。由于缺乏过氧化酶体而导致的人类疾病 这些疾病是严重的多系统疾病，称为过氧化物酶体生物发生障碍， Zellweger谱系障碍(PBD-ZSD)说明了人类对过氧化物酶体的需求 健康。来自PBD-ZSD研究的见解已被应用于常见疾病，如 阿尔茨海默氏症。为了探索PBD-ZSD背后的分子机制，我使用了 果蝇基因组学、非靶向代谢组学和基因技术。我是一个敬业的人 内科医生-科学家，致力于PBD-ZSD的研究，已经做出了几个 贡献。首先，我使用代谢组学定义了一种生化异常或 “PBD-ZSD代谢体”是这些疾病的特征特征，有趣的是包括 减少的鞘磷脂，一种以前未被认识的PBD-ZSD的生物标志物。第二，我的实验室有 在果蝇身上使用创新的基因技术来进一步探索过氧化物体的后果 神经元的生物学。例如，在果蝇X的一个大的正向遗传屏幕上- 染色体我们在体内发现了改变过氧化物体的新基因，我们已经展示了这些 是神经疾病的候选基因。最后，利用基因组学，我开发了一条轨迹 诊断具有新的或独特的基因突变的未诊断个体的记录 ACOX1，DNM1L，PEX1和PEX16，这些研究指出了新的遗传机制 过氧酶体疾病。根据我对神经鞘磷脂的研究，我推测过氧化物酶 功能障碍导致鞘磷脂侧链组成改变，从而导致 PBD-ZSD患者神经功能受损。我还建议，根据动物模型研究， 在神经系统功能的发育和衰老过程中，都需要过氧化酶体。 最后，我的初步数据表明从头开始的突变会影响过氧化物体基因， 这些基因在传统上被认为是“常染色体隐性遗传”，可能是 过氧酶体疾病。在这项建议中，我们使用了临床研究，独特的模式生物技术 以及基因组和代谢技术来验证这些假说并推进对PBD的研究- ZSD有助于更好地诊断、治疗和提高患者的生活质量。