Role of NGF in Familial Dysautonomia

描述（由申请人提供）：尽管有证据表明神经营养因子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变中神经营养功能障碍的潜在机制及其与疾病过程的相关性仍未得到很好的定义。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，伴有交感神经节和感觉神经节中神经元数量异常减少。这种疾病是由编码IKAP的基因Ikbkap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绘疾病的潜在机制。我们已经通过突变小鼠Ikbkap基因同源物产生了FD的小鼠模型。到目前为止，这是唯一的模型，概括了疾病的分子和病理学特征，因此代表了一个宝贵的和独特的工具，以确定疾病神经病理学的机制。根据我们的初步结果，神经营养活性降低，血清和成纤维细胞从FD患者，IKAP调节弗林蛋白酶（在胚胎发育过程中的NGF加工所需的酶）的表达，并抑制NGF活性重演疾病的神经病理学在体内的研究结果，我们假设，减少神经生长因子介导的神经营养支持FD神经病理学的基础。使用分子、生物化学、细胞和遗传方法，我们将（1）检验在我们的FD模型中NGF的转录调节受损的假设，（2）检验在我们的FD小鼠模型中NGF的生物活性降低是由于受损的pro-NGF加工和信号传导的假设，（3）检验NGF和/或弗林蛋白酶的过表达挽救FD小鼠发育中的外周神经系统中的神经元细胞损失的假设。提出的分析不仅将提供进一步的信息FD的机制，但也洞察潜在的治疗干预。它也将增强我们对正常周围神经系统发育和维持的理解。 公共卫生相关性：周围神经病影响很大一部分人群，并被分类为炎症性、毒性、代谢性（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，且不可避免地是致命的.了解这种疾病的机制将为FD和其他周围神经系统疾病的潜在新的治疗干预提供见解。

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.