Role of NGF in Familial Dysautonomia

描述(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重要作用，但在不同人类周围神经疾病中潜在的神经营养功能障碍的机制以及它与疾病过程的相关性仍然没有很好的确定。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。受FD影响的个体在出生时就表现出周围神经系统功能障碍，伴随着交感神经节和感觉神经节中神经元数量的异常减少。这种疾病是由编码IKAP的基因Ikbkap突变引起的。随着引起FD的基因的确定，现在可以更清楚地描述这种疾病的潜在机制。我们已经通过突变小鼠的Ikbkap基因同源基因产生了一个FD的小鼠模型。到目前为止，这是唯一一个概括了疾病的分子和病理特征的模型，因此是确定疾病神经病理学基础机制的宝贵而独特的工具。根据我们的初步结果，我们发现FD患者血清和成纤维细胞的神经营养活性降低，IKAP调节Furin(胚胎发育中NGF加工所需的酶)的表达，以及抑制NGF活性在体内概括了疾病的神经病理学，我们假设减少NGF介导的神经营养支持是FD神经病理的基础。利用分子、生化、细胞和遗传学方法，我们将(1)检验我们的FD模型中NGF转录调控受损的假说，(2)检验我们的FD小鼠模型中NGF生物活性降低是由于NGF前体处理和信号受损所致的假说，(3)检验NGF和/或Furin的过度表达可以挽救FD小鼠发育中的周围神经系统神经细胞丢失的假说。建议的分析不仅将为FD的潜在机制提供进一步的信息，而且还将为潜在的治疗干预提供洞察力。此外，它还将增进我们对正常周围神经系统发育和维护的了解。公共卫生相关性：周围神经病影响到相当一部分人口，并被归类为炎症性、中毒性、代谢性(糖尿病)和遗传性神经病。家族性自主神经异常(FD)是最常见的遗传性神经病，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的治疗干预措施提供见解。

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.