权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Therapeutic Development in Segmental Demyelination

节段性脱髓鞘的治疗进展

基本信息

批准号：
9277192
负责人：
JUN LI
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
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：
2016-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9277192
关键词：
Action Potentials Adult Alleles Axon Blindness Buffers Cells Charcot-Marie-Tooth Disease Chronic Inflammatory Demyelinating Polyneuropathy Defect Demyelinating Diseases Demyelinating Polyneuropathy Demyelinations Development Down-Regulation Dynamin Excision Exhibits Failure Flow Cytometry Guanosine Triphosphate Phosphohydrolases Guillain-Barré Syndrome Homeostasis Human Impairment Knockout Mice Lead Ligands Limb structure Lysosomes Membrane Methods Missense Mutation Molecular Multifocal Motor Neuropathy Multiple Sclerosis Mus Mutation Myelin NAADP Nerve Nerve Degeneration Neural Conduction Neurologic Neurons Neuropathy Organelles Paralysed Pathogenicity Pathologic Pathology Patients Phosphatidylinositols Phospholipids Phosphoric Monoester Hydrolases Play Principal Investigator Probability Protein Biosynthesis Proteins Publications Role Schwann Cells Sensory Shunt Device Signal Pathway Specificity Surface Syndrome Testing Therapeutic Therapeutic Intervention disability in vivo inorganic phosphate loss of function loss of function mutation mutant nerve injury nervous system disorder novel patient subsets prevent protein complex public health relevance remyelination scaffold therapeutic development trafficking

项目摘要

DESCRIPTION (provided by applicant): Demyelination shunts depolarizing current out of the nerve. As a result, nerve conduction of action potentials can be slowed or even eliminated. The later is known as conduction block. This change causes neurological disabilities such as sensory loss, vision loss, and limb paralysis in a variety of neurological diseases. We have found that patients and mice with FIG4 deficiency develop a demyelinating neuropathy. This demyelination closely recapitulates features in acquired demyelinating diseases. The FIG4-deficient cells exhibit lysosomal membrane fission defect with an abnormally suppressed efflux of intralysosomal Ca2+ through a lysosomal Ca2+ channel. These observations lead us to propose the hypothesis below. Hypothesis: FIG4 deficiency deactivates Ca2+-channels on lysosomal membranes and prevents Ca2+ release from lysosomes. This, in turn, impairs lysosomal membrane trafficking (lysosomal fission defect), leading to segmental demyelination. Toward this end, we propose the following specific aims. Specific Aim 1. To test the hypothesis that FIG4 deficiency suppresses lysosomal fission by blocking the efflux of intralysosomal Ca2+ in myelinating Schwann cells. Specific Aim 2. To determine whether FIG4-deficiency in Schwann cell sensitizes the cell to demyelination. In this aim, we will utilize Fig4 conditional knockout mice to examine how the impaired lysosomal Ca2+-homeostasis in Fig4-/- Schwann cells may sensitize the cells to demyelination. Specific Aim 3. To test the hypothesis that FIG4 in myelinating Schwann cells is required for remyelination. Significance of lysosomal membrane trafficking in de/remyelination is essentially unexplored. Our results have demonstrated a novel signaling pathway in FIG4 deficiency that appears to be critical in lysosomal membrane trafficking and demyelination. Since demyelination in Fig4-/- nerves recapitulates key features of acquired demyelinating diseases, results from this project are also relevant to other acquired demyelinating disorders. Furthermore, our preliminary results suggest a high probability in developing therapeutic interventions for demyelination in FIG4 deficiency.

描述（由申请人提供）：脱髓鞘将去极化电流分流出神经。结果，动作电位的神经传导可以减慢甚至消除。后者称为传导阻滞。这种变化会导致多种神经系统疾病中的感觉丧失、视力丧失、肢体瘫痪等神经功能障碍。我们发现，FIG4 缺陷的患者和小鼠会出现脱髓鞘性神经病。这种脱髓鞘密切再现了获得性脱髓鞘疾病的特征。 Fig4 缺陷细胞表现出溶酶体膜裂变缺陷，溶酶体内 Ca2+ 通过溶酶体 Ca2+ 通道的流出异常受到抑制。这些观察结果使我们提出以下假设。假设：FIG4 缺陷会使溶酶体膜上的 Ca2+ 通道失活并阻止 Ca2+ 从溶酶体中释放。这反过来又损害溶酶体膜运输（溶酶体裂变缺陷），导致节段性脱髓鞘。为此，我们提出以下具体目标。具体目标 1. 检验以下假设：FIG4 缺陷通过阻断有髓鞘雪旺细胞中溶酶体内 Ca2+ 的流出来抑制溶酶体裂变。具体目标2.确定雪旺细胞中FIG4缺陷是否会使细胞对脱髓鞘敏感。为此，我们将利用Fig4条件敲除小鼠来检查Fig4-/-雪旺细胞中受损的溶酶体Ca2+稳态如何使细胞对脱髓鞘敏感。具体目标 3. 检验有髓鞘雪旺细胞中的Fig4 是髓鞘再生所必需的假设。溶酶体膜运输在脱髓鞘/髓鞘再生中的重要性基本上尚未被探索。我们的结果表明，FIG4 缺陷中存在一种新的信号通路，该通路似乎在溶酶体膜运输和脱髓鞘中至关重要。由于 Fig4-/- 神经中的脱髓鞘概括了获得性脱髓鞘疾病的关键特征，因此该项目的结果也与其他获得性脱髓鞘疾病相关。此外，我们的初步结果表明很有可能开发出针对Fig4 缺乏症脱髓鞘的治疗干预措施。