Genetic restoration of IKAP as a tool to study Familial Dysautonomia

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， 交感神经节和感觉神经节的神经元数量异常低，随着时间的推移进一步下降。的 疾病是由基因IKBKAP突变引起的，该突变导致IKBKAP基因表达的显著降低。 它所编码的蛋白质叫做IKAP。 由于IKAP显然是几个细胞过程所必需的，并且FD是一个渐进的过程， 对于神经退行性疾病，最近许多努力集中在鉴定和测试 增加IKAP表达，希望增加IKAP水平将阻止疾病进展和/或 逆转某些疾病的表型。然而，由于FD具有很强的发展成分， 尚不清楚增加IKAP表达在多大程度上可以阻止疾病进展或显着改善病情 受影响个体的临床特征和生活质量。虽然测试增加IKAP的化合物 从长远来看，小鼠模型或患者中的水平可能会回答这个问题，决定何时 应开始治疗，并确定治疗成功所需的最佳IKAP水平 代表了一种巨大的努力。此外，这种药物的长期毒性全身副作用的可能性 化合物可能掩盖其有益效果。 使用Cre-loxP重组系统，我们已经产生了一种独特的FD小鼠模型， 它不仅概括了大量的疾病表型特征，而且还可以用于遗传学上的研究。 随意恢复IKAP表达，从而避免其他策略的脱靶效应。有了这个独特的工具， 另一方面，我们建议在不同的时间点使用一种新的方法来评估整体恢复IKAP表达的效果。 他莫昔芬诱导型Cre转基因系。 该申请的完成将揭示旨在增加IKAP的FD疗法的全部潜力 表达水平，指导未来的研究走向互补的治疗方法，并允许进一步的研究。 了解FD的潜在机制。

Familial Dysautonomia (FD) is the most prevalent hereditary autonomic and sensory neuropathy. Individuals affected with FD display dysfunction of the peripheral nervous system already at birth accompanied by abnormally low neuronal numbers in sympathetic and sensory ganglia, which further decline over time. The disorder is caused by mutations in the gene IKBKAP that lead to significant decrease in expression of the protein it encodes, called IKAP. Since IKAP is apparently needed for several cellular processes and FD is a progressive neurodegenerative disorder, much effort has been recently focused in identifying and testing compounds that increase IKAP expression, with the hope that increasing IKAP levels will halt the disease progression and/or reverse some of the disease phenotypes. However, since FD has a strong developmental component, it is unclear to what extent increasing IKAP expression may stop disease progression or significantly improve the clinical features and quality of life of affected individuals. Although testing compounds that increase IKAP levels in mouse models or in patients may answer this question in the long run, determining the timing when the treatments should be initiated and the optimal level of IKAP required for the treatment to be successful represents a Herculean effort. In addition, the possibility of long-term toxic systemic side-effects of such compounds may mask their beneficial effects. Using the Cre-loxP system of recombination, we have generated a unique mouse model for FD that not only recapitulates a large number of the disease phenotypic features, but can also be used to genetically restore IKAP expression at will, thus avoiding the off-target effects of other strategies. With this unique tool in hand, we propose to assess the effects of restoring IKAP expression globally at different time-points using a tamoxifen-inducible Cre transgenic line. Completion of this application will uncover the full potential of FD therapies that aim at increasing IKAP expression levels, guide future research towards complementary therapeutic approaches, and allow for further understanding of the mechanisms underlying FD.