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：
8514090
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/8514090
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.

描述（由申请人提供）：该提案描述了为期五年的指导实验室培训经验，旨在实现临床相关基础科学领域的独立学术生涯。申请人拥有医学博士学位，并已完成儿科专业培训和委员会认证，目前正在完成医学遗传学的子专业培训。职业发展计划包括一段时期的指导研究培训，其中包括学习研究技术和概念，并辅以教学培训、研讨会、实验室会议、期刊俱乐部、国内和国际会议、咨询委员会以及与导师的会议。研究环境提供了最好的智力环境和最好的技术，并为申请人提供了学习电子显微镜和电生理学等强大技术的机会。该研究旨在通过关注果蝇的过氧化物酶体生物发生，提高我们对分子水平上的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普遍存在的细胞器，由 pex 基因编码的一组进化上保守的蛋白质产生。人类 pex 位点突变会导致过氧化物酶体生物发生障碍 (PBD)，这是一种具有毁灭性神经系统后果的疾病。 PBD 的神经系统并发症已得到表征，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，可用于研究果蝇过氧化物酶体的工具非常少，因此我们将生成额外的工具，以便对 pex2 和 pex16 进行精确、彻底的分析，包括无效等位基因、标记基因组构建体和表征分析过氧化物酶体的结构和功能。我们将通过检验过氧化物酶体损失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，我们将基于显示 pex16 P 元件插入突变体电生理缺陷的初步数据，通过定义缺陷的过氧化物酶体生物发生导致突触传递中的胞吐缺陷的机制。这项研究将使人们更广泛地了解过氧化物酶体生物发生对神经系统的影响。这可能对患有过氧化物酶体疾病的患者具有临床意义。这项研究还将在致力于培训申请人作为独立科学家进一步开展这项研究的环境中进行。