Genetic restoration of IKAP as a tool to study Familial Dysautonomia

IKAP 的遗传恢复作为研究家族自主神经功能障碍的工具

• 批准号: 9804600
• 负责人: IOANNIS DRAGATSIS
• 金额: $ 41.8万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9804600
• 关键词: Address; Adolescent; Adult; Affect; Age; Age-Months; Age-Years; Area; Attenuated; Behavioral Research; Biomedical Research; Birth; Caring; Cell physiology; Clinic; Clinical; Clinical Research; Development; Disease; Disease Progression; Embryo; Familial Dysautonomia; Functional disorder; Funding; Future; Genes; Genetic; Genetic Recombination; Grant; Hand; Health; Hereditary Sensory and Autonomic Neuropathies; Hospitalization; Human; Impairment; Individual; Intervention; Laboratory Research; Lead; Life; Masks; Medical; Methodology; Methods; Modeling; Mus; Mutation; Neonatal; Neurodegenerative Disorders; Neurons; One-Step dentin bonding system; Patients; Peripheral Nervous System; Pharmacotherapy; Phenotype; Physiological; Point Mutation; Pregnancy; Proteins; Quality of life; Research; Sensory Ganglia; Source; Sympathetic Ganglia; Tamoxifen; Techniques; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; United States National Institutes of Health; Up-Regulation; Weaning; associated symptom; base; causal variant; cell type; cohort; disease phenotype; effective therapy; high reward; high risk; improved; mouse model; novel; postnatal; progressive neurodegeneration; protein expression; recombinase-mediated cassette exchange; restoration; side effect; therapeutic evaluation; therapy outcome; tool

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.

家族性动物障碍（FD）是最普遍的遗传自主神经和感觉神经病。 外周神经系统的FD显示功能障碍的人已经出生时 通过同情和感觉神经节中的神经元数异常，随着时间的流逝进一步下降。这 疾病是由基因IKBKAP突变引起的，导致表达的显着降低 蛋白质它编码，称为IKAP。 由于显然需要几个蜂窝过程IKAP，而FD是一个进行的 神经退行性障碍，最近努力集中在识别和测试化合物上 增加IKAP表达，希望增加的IKAP水平会停止疾病进展和/或 逆转一些疾病表型。但是，由于FD具有强大的发展组成部分，因此 不清楚IKAP表达在多大程度上可能阻止疾病进展或显着改善 受影响个体的临床特征和生活质量。尽管测试化合物增加了IKAP 从长远来看，鼠标模型或患者中的水平可能会回答这个问题，确定时间 应启动治疗方法，并获得成功的最佳IKAP水平 代表艰苦的努力。另外，这种可能的长期有毒系统副作用的可能性 化合物可能会掩盖它们的有益作用。 使用CRE-LoxP重组系统，我们为FD生成了独特的鼠标模型，而不是 仅概括了大量疾病表型特征，但也可以用于基因 随意恢复IKAP的表达，从而避免了其他策略的脱靶影响。有了这个独特的工具 手，我们建议使用A以不同的时间点评估全球恢复IKAP表达的效果 他莫昔芬可诱导的CRE转基因线。 该应用程序的完成将揭示旨在增加IKAP的FD疗法的全部潜力 表达水平，指导未来的研究采用互补的治疗方法，并允许进一步 了解FD的基础机制。