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起着至关重要的作用，但不同人类周围神经病变中神经营养功能障碍的机制及其与疾病过程的相关性仍未得到很好的定义。家族性自主神经异常（FD）是最常见的遗传性自主神经和感觉神经病变。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Ikbkap基因的突变引起的，该基因编码IKAP。随着导致FD的基因的鉴定，该疾病的潜在机制现在可以更清楚地描绘出来。我们通过突变小鼠Ikbkap基因同源物建立了FD小鼠模型。迄今为止，这是唯一一个概括了该疾病的分子和病理特征的模型，因此代表了确定该疾病神经病理学基础机制的宝贵和独特的工具。根据我们的初步结果，FD患者血清和成纤维细胞中的神经营养活性降低，IKAP调节furin（胚胎发生过程中NGF加工所需的酶）的表达，以及NGF活性的抑制概括了体内疾病的神经病理学，我们假设NGF介导的神经营养支持减少是FD神经病理学的基础。使用分子、生化、细胞和遗传学方法，我们将(1)验证我们的FD模型中NGF的转录调控受损的假设；(2)验证FD小鼠模型中NGF生物活性降低是由于NGF前加工和信号传导受损的假设；(3)验证NGF和/或furin的过度表达挽救FD小鼠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为FD的机制提供进一步的信息，而且还将为潜在的治疗干预提供见解。它也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：周围神经病变影响很大一部分人群，分为炎症性、毒性、代谢性（糖尿病）和遗传性神经病变。家族性自主神经异常（FD）是最常见的遗传性神经病变，不可避免地是致命的。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。

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.