Neuronal Mechanisms of Peroxisomal Biogenesis Defects in Drosophila

果蝇过氧化物酶体生物发生缺陷的神经机制

基本信息

批准号：
8223838
负责人：
Michael Francis Wangler
金额：
$ 14.58万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8223838
关键词：
Adult Advisory Committees Affect Alleles Basic Science Behavioral Assay Biochemical Biochemistry Biogenesis Biological Biological Assay Biological Models Biological Process Board Certification Cells Chemistry Clinical Data Defect Development Plans Disease Doctor of Medicine Drosophila genus Drosophila melanogaster Dynamin Electron Microscopy Electrons Electrophysiology (science)Environment Eukaryota Excision Exocytosis Functional disorder Gene Mutation Gene Proteins Genes Genomics Goals Human International Journals Laboratories Lead Learning Ligase Link Longevity Measures Medical Genetics Membrane Fusion Mentors Mitochondria Molecular Morphology Mutation Names Nervous system structure Neurologic Neuromuscular Junction Neurons Organelles Oxygen Consumption Patients Pediatrics Peroxisomal Disorders Phenotype Phosphorus Plasmalogens Process Protein Analysis Proteins Recording of previous events Research Research Personnel Research Technics Research Training Respiratory Chain Retina Role Scientist Series Shapes Structure Supplementation Synapses Synaptic Transmission Synaptic Vesicles Techniques Technology Testing Training Transmission Electron Microscopy Vesicle Work base career career development clinically relevant cysteine string protein design effective therapy experience fly human disease improved locomotor deficit loss of function mutation medical specialties meetings mutant neuropathology null mutation peroxisome research study synaptotagmin tool vesicle-associated membrane protein

项目摘要

DESCRIPTION (provided by applicant): The proposal describes a five-year mentored laboratory training experience designed to lead to an independent academic career in clinically-relevant basic science. The applicant holds an M.D. degree, and has completed specialty training and board certification in pediatrics and is currently completing sub-specialty training in Medical Genetics. The career development plan includes a period of mentored research training which will include learning research techniques and concepts supplemented by didactic training, seminars, lab meetings, journal clubs, national and international meetings, an advisory committee and meetings with the mentor. The research environment provides the best intellectual environment and the best technology available and gives the applicant the opportunity to be guided in learning powerful techniques such as electron microscopy and electrophysiology. The research seeks to improve our understanding of peroxisomal biogenesis disorders at the molecular level by focusing on peroxisomal biogenesis in Drosophila. Peroxisomes are ubiquitous organelles in eukaryotes, generated by a set of evolutionarily conserved proteins encoded by the pex genes. Mutations in pex loci in humans lead to Peroxisomal Biogenesis Disorders (PBD), diseases with devastating neurologic consequences. The nervous system complications of PBD have been characterized but their mechanism is not known. Drosophila provides a good model system to add to our knowledge of peroxisomal biogenesis defects. Very little is known about the pex genes in Drosophila. We have selected pex2 and pex16 for analysis. Because of the novelty of this approach very minimal tools are available to study peroxisomes in Drosophila, we will therefore generate additional tools to allow for a precise and thorough analysis of pex2 and pex16 including null alleles, tagged genomic constructs, and assays for the characterization of peroxisome structure and function. We will explore the interaction of peroxisomes with other organelles by testing the hypothesis that peroxisomal loss affects mitochondrial function. Finally, we will build on our preliminary data showing electrophysiologic defects in pex16 P-element insertion mutants by defining the mechanisms by which defective peroxisomal biogenesis lead to exocytic defects in synaptic transmission. This research will create a broader understanding of the effect of peroxisomal biogenesis on the nervous system. This could have clinical implications for patients with peroxisomal disorders. This research will also occur in an environment dedicated to training the applicant to pursue this research further as an independent scientist. PUBLIC HEALTH RELEVANCE: This research studies a group of diseases in which the patient lacks an important cellular organelle named peroxisomes leading to problems in body chemistry. Researchers use fruit flies with similar genetic alterations to study the problems that result from lacking peroxisomes. The research could lead to a better understanding of these diseases for which there are no effective treatments.

描述（由申请人提供）：该提案描述了一项为期五年的实验室培训经验，旨在导致与临床相关的基础科学领域的独立学术职业。申请人拥有医学博士学位，并完成了儿科专业培训和董事会认证，目前正在完成医学遗传学的亚专业培训。职业发展计划包括一段指导的研究培训，其中包括学习研究技术和教学培训，研讨会，实验室会议，期刊俱乐部，国家和国际会议，咨询委员会以及与导师会议的概念。研究环境提供了最佳的智力环境和最佳的技术，并使申请人有机会学习强大的技术，例如电子显微镜和电生理学。该研究旨在通过关注果蝇的过氧化物酶体生物发生，以提高我们对分子水平过氧化物酶体生物发生障碍的理解。过氧化物酶体是真核生物中无处不在的细胞器，由PEX基因编码的一组进化保守的蛋白质产生。人类PEX基因座的突变导致过氧化物酶体生物发生障碍（PBD），具有毁灭性神经系统后果的疾病。 PBD的神经系统并发症已被表征，但其机制尚不清楚。果蝇提供了一个良好的模型系统，以增加我们对过氧化物酶体生物发生缺陷的了解。关于果蝇中的PEX基因知之甚少。我们选择了PEX2和PEX16进行分析。由于这种方法的新颖性，非常最小的工具可用于研究果蝇中的过氧化物酶体，因此我们将生成其他工具，以允许对PEX2和PEX16进行精确而彻底的分析，包括无效等位基因，标记的基因组构建体，以及用于表征过氧化物群结构和功能的测定法。我们将通过测试过氧化物酶体损失会影响线粒体功能的假设来探索过氧化物酶体与其他细胞器的相互作用。最后，我们将建立在初步数据的基础上，显示PEX16 p元素插入突变体中电生理缺陷，通过定义过氧化物酶体生物发生有缺陷导致突触传播中的外生缺陷的机制。这项研究将对过氧化物酶体生物发生对神经系统的影响有更广泛的了解。这可能对过氧化物酶疾病患者具有临床意义。这项研究也将发生在致力于培训申请人作为独立科学家进一步探讨这项研究的环境中。公共卫生相关性：该研究研究一组患者缺乏重要的细胞细胞器，称为过氧化物酶体导致人体化学问题。研究人员使用具有类似遗传改变的水果果蝇来研究缺乏过氧化物酶体引起的问题。该研究可能会更好地理解这些疾病，这些疾病没有有效的治疗方法。