Role of NGF in Familial Dysautonomia

NGF 在家族性自主神经功能障碍中的作用

基本信息

批准号：
7795713
负责人：
IOANNIS DRAGATSIS
金额：
$ 31.62万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7795713
关键词：
Address Affect Autonomic ganglion Binding Biochemical Biological Biological Assay Birth Cells Code Complex Cyclic AMP Development Diabetes Mellitus Disease Dysautonomias EMSA Embryo Embryonic Development Enzymes Exhibits Familial Dysautonomia Fibroblasts Functional disorder Genes Genetic Genetic Crosses Genetic Transcription Hereditary Sensory and Autonomic Neuropathies Homologous Gene Human Immunohistochemistry In Situ Hybridization Individual Inflammatory Knockout Mice Maintenance Mediating Messenger RNA Metabolic Modeling Molecular Mus Mutant Strains Mice Mutate Mutation Nerve Neurites Neuroglia Neurons Newborn Infant Pathology Patients Perinatal Peripheral Nervous System Peripheral Nervous System Diseases Phosphorylation Play Population Process Regulator Genes Relative (related person)Role Sensory Sensory Ganglia Serum Signal Pathway Signal Transduction Skin Source Staging Testing Therapeutic Intervention Time Tissues Transcriptional Regulation Transgenic Mice Work base computerized data processing hereditary neuropathy in vivo insight keratinocyte mouse model mutant nerve supply nervous system development neuron loss neuronal survival neuropathology neurotrophic factor novel therapeutic intervention overexpression postnatal promoter public health relevance tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Despite evidence that neurotrophins play an essential role in the development and maintenance of the peripheral nervous system, the mechanisms underlying neurotrophic dysfunction in different human peripheral neuropathies as well as its relevance to the disease process are still not well defined. Familial Dysautonomia (FD) is the most frequent hereditary autonomic and sensory neuropathy. Individuals affected with FD display dysfunction of the peripheral nervous system already at birth accompanied by abnormally low numbers of neurons in sympathetic and sensory ganglia. The disorder is caused by mutations in the gene Ikbkap, which encodes IKAP. With the identification of the gene that causes FD, the mechanisms underlying the disease can now be more clearly delineated. We have generated a mouse model for FD by mutating the mouse Ikbkap gene homolog. To date this is the only model that recapitulates the molecular and pathological features of the disease and thus represents an invaluable and unique tool to determine the mechanisms underlying the disease neuropathology. Based on our preliminary results, the findings that neurotrophic activity is reduced in serum and fibroblasts from FD patients, that IKAP regulates expression of furin (the enzyme required for NGF processing in embryogenesis), and that inhibition of NGF activity recapitulates the disease neuropathology in vivo, we hypothesize that reduced NGF-mediated neurotrophic support underlies FD neuropathology. Using molecular, biochemical, cellular, and genetic approaches we will (1) test the hypothesis that transcriptional regulation of NGF is impaired in our model of FD, (2) test the hypothesis that the reduced biological activity of NGF in our FD mouse model is due to impaired pro-NGF processing and signaling, (3) test the hypothesis that over-expression of NGF and/or furin rescues neuronal cell loss in the developing peripheral nervous system of FD mice. The analyses proposed will not only provide further information into mechanisms underlying FD, but also insight for potential therapeutic intervention. Also it will enhance our understanding of the normal peripheral nervous system development and maintenance. PUBLIC HEALTH RELEVANCE: Peripheral neuropathies affect a significant fraction of the population and are classified as inflammatory, toxic, metabolic (diabetes mellitus) and hereditary neuropathies. Familial Dysautonomia (FD) is the most frequent hereditary neuropathy, and is inevitably fatal. Understanding the mechanisms underlying this disorder will provide insights for potential new therapeutic interventions for FD and for other peripheral nervous system disorders.

描述（由申请人提供）：尽管有证据表明神经营养蛋白在周围神经系统的发育和维持中发挥重要作用，但不同人类周围神经病中神经营养功能障碍的机制及其与疾病过程的相关性仍然没有明确定义。家族性自主神经功能障碍（FD）是最常见的遗传性自主神经和感觉神经病。患有 FD 的个体在出生时就表现出周围神经系统功能障碍，并伴有交感神经节和感觉神经节神经元数量异常减少。这种疾病是由编码 IKAP 的 Ikbkap 基因突变引起的。随着导致 FD 的基因的鉴定，现在可以更清楚地描述该疾病的机制。我们通过突变小鼠 Ikbkap 基因同源物生成了 FD 小鼠模型。迄今为止，这是唯一概括该疾病的分子和病理特征的模型，因此代表了确定疾病神经病理学潜在机制的宝贵且独特的工具。根据我们的初步结果，发现 FD 患者的血清和成纤维细胞中的神经营养活性降低，IKAP 调节弗林蛋白酶（胚胎发生过程中 NGF 加工所需的酶）的表达，以及 NGF 活性的抑制在体内概括了疾病的神经病理学，我们假设 NGF 介导的神经营养支持的减少是 FD 神经病理学的基础。使用分子、生化、细胞和遗传方法，我们将 (1) 检验 NGF 转录调控在我们的 FD 模型中受损的假设，(2) 检验以下假设：NGF 在我们的 FD 小鼠模型中生物活性降低由于 pro-NGF 加工和信号传导受损，(3) 检验 NGF 和/或弗林蛋白酶的过度表达可挽救 FD 小鼠发育中的周围神经系统中神经元细胞损失的假设。所提出的分析不仅将提供有关 FD 潜在机制的更多信息，而且还将为潜在的治疗干预提供见解。它还将增强我们对正常周围神经系统发育和维护的理解。公共卫生相关性：周围神经病影响很大一部分人群，分为炎症性神经病、毒性神经病、代谢性神经病（糖尿病）和遗传性神经病。家族性自主神经功能障碍 (FD) 是最常见的遗传性神经病，并且不可避免地致命。了解这种疾病的潜在机制将为 FD 和其他周围神经系统疾病的潜在新治疗干预提供见解。