Role of NGF in Familial Dysautonomia

NGF 在家族性自主神经功能障碍中的作用

• 批准号: 7435875
• 负责人: IOANNIS DRAGATSIS
• 金额: $ 31.94万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 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/7435875
• 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; Nerve Growth Factor 1; Nerve Growth Factor Pathway; Neurites; Neuroglia; Neurons; Newborn Infant; Numbers; Pathology; Patients; Perinatal; Peripheral Nervous System; Peripheral Nervous System Diseases; Phosphorylation; Play; Polymerase Chain Reaction; Population; Process; Protein Overexpression; Public Health; 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 therapeutics; postnatal; promoter; tool; transcription factor

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展和维持中起着至关重要的作用，但在不同人类外周神经病中神经营养功能障碍的机制以及与疾病过程相关的机制仍然没有很好地定义。家族性动力障碍（FD）是最常见的遗传自主神经和感觉神经病。受FD表现出的外周神经系统功能障碍的个体已经出生时伴随着同情和感觉神经节中异常数量的神经元。该疾病是由编码IKAP的基因IKBKAP中的突变引起的。通过鉴定导致FD的基因，现在可以更清楚地描绘出疾病的基础机制。我们通过突变小鼠IKBKAP基因同源物生成了FD的小鼠模型。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基础机制的宝贵和独特的工具。 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基础FD神经病理学。使用分子，生化，细胞和遗传学方法，我们将（1）检验以下假设：在我们的FD模型中，NGF的转录调节受到损害，（2）检验以下假说：NGF在FD小鼠模型中降低NGF的生物学活性降低，这是由于降低了ngf小鼠模型，这是由于降低了NGF的rec Resiv and-ngf处理和信号（3）过度的ng（3）过度ngf and（3） FD小鼠发育中的周围神经系统中的神经元细胞丧失。提出的分析不仅将提供进一步的信息，以了解FD潜在的机制，还将提供潜在治疗干预的见解。这也将增强我们对正常外周神经系统发展和维护的理解。 公共卫生相关性：周围神经病影响很大一部分人群，并被归类为炎症，有毒，代谢（糖尿病）和遗传神经病。家族性动物障碍（FD）是最常见的遗传神经病，不可避免地致命。了解这种疾病的基础机制将为FD和其他周围神经系统疾病的潜在新治疗干预提供见解。