The prohibitin family and their function in myelination and axonal health

抑制素家族及其在髓鞘形成和轴突健康中的功能

基本信息

批准号：
9259560
负责人：
M. Laura Feltri
金额：
$ 34.1万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9259560
关键词：
Adhesions Adult Affect Age-Months Antibodies Apoptosis Axon Basal lamina Binding CCL2 gene Cell Communication Cell Nucleus Cell Proliferation Cell membrane Cells Cellular Metabolic Process Charcot-Marie-Tooth Disease Chimeric Proteins Complex Data Defect Demyelinations Development Diabetes Mellitus Disease FRAP1 gene Failure Family Genus Hippocampus Health In Vitro Infiltration Inherited Integral Membrane Protein JUN gene Knockout Mice Lead Location Maintenance Mass Spectrum Analysis Measures Mediating Mitochondria Molecular Molecular Chaperones Morphology Mus Myelin Myelin Sheath Nerve Nerve Regeneration Neural Conduction Neuroglia Neuromuscular Diseases Neuropathy Oligodendroglia Oxidative Stress Pain Pathway interactions Patients Peripheral Peripheral Nervous System Diseases Play Process Production Protein Family Proteins Proto-Oncogene Proteins c-akt Radial Respiration Role Schwann Cells Series Signal Transduction Site Sorting - Cell Movement Speed Structure Surface System Techniques Technology Testing Time Wallerian Degeneration abstracting axonal degeneration base behavioral study disability dysmyelination in vivo innovation macrophage member mitochondrial dysfunction myelination neurophysiology novel prohibitin response senescence

项目摘要

Abstract. Myelin is required for conduction of nerve impulses and to protect axons. Impaired formation or destruction of myelin causes a series of debilitating diseases. Diseases of peripheral myelin are among the most common neuromuscular disorders and cause significant disability. The fundamental mechanisms that underlie how peripheral myelin- forming Schwann cells differentiate and myelinate, how they maintain a healthy myelin sheath and how they support axons are only partially understood. Using an innovative system to study cell-cell interactions we recently identified a new family of molecules, the prohibitins, which are required in Schwann cells in vivo to interact with axons, myelinate and maintain healthy myelin and axons. Deletion of prohibitins in Schwann cells in mice causes dys-myelination, de-myelination and axonal degeneration. Prohibitins are conserved transmembrane proteins found in mitochondria, plasmamembranes and nuclei. They function as signaling adaptors and chaperones and they are involved in adhesion, signaling, and senescence. We propose to use a combination of state-of-the art and innovative techniques in vivo and in vitro to test the hypotheses that prohibitin-2 in Schwann cells is part of a plasma membrane signaling complex that interact with axons early in development, while a prohibitin-1/prohibitin-2 complex in the mitochondria maintains myelin and axon integrity. We will identify prohibitins interactors and discover how prohibitins regulate senescence, proteostasis and mitochondria function in Schwann cells. These data are likely to define the novel function of prohibitins in myelination and axon protection, and may reveal new molecular mechanisms that are important for axo-glial interactions during peripheral neuropathies.

抽象的。髓磷脂是传导神经冲动和保护轴突所必需的。受损髓磷脂的形成或破坏会导致一系列使人衰弱的疾病。疾病外周髓磷脂是最常见的神经肌肉疾病之一，并导致严重残疾。外周髓鞘质的基本机制雪旺细胞分化和髓鞘形成，它们如何维持健康的髓鞘鞘以及它们如何支撑轴突仅被部分了解。使用创新的研究细胞与细胞相互作用的系统，我们最近发现了一个新的分子家族，抑制素，是雪旺细胞体内与轴突、髓鞘质相互作用所必需的维持健康的髓磷脂和轴突。小鼠雪旺细胞中抑制素的缺失会导致髓鞘形成障碍、脱髓鞘和轴突变性。抑制素是保守的跨膜蛋白存在于线粒体、质膜和细胞核中。他们作为信号适配器和伴侣，它们参与粘附、信号传导、和衰老。我们建议结合最先进和创新体内和体外技术测试雪旺细胞中抑制素 2 的假设质膜信号复合体的一部分，在发育早期与轴突相互作用，而线粒体中的抑制素 1/抑制素 2 复合物则维持髓磷脂和轴突正直。我们将识别禁止素相互作用者并发现禁止素如何调节雪旺细胞中的衰老、蛋白质稳态和线粒体功能。这些数据很可能定义抑制素在髓鞘形成和轴突保护中的新功能，并可能揭示新的分子机制对外周神经胶质细胞相互作用很重要神经病。