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

基本信息

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
项目类别：
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

项目摘要

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中的神经元数量异常低，并且随着时间的推移进一步减少。这该疾病是由 IKBKAP 基因突变引起的，导致 IKBKAP 基因表达显着下降。它编码的蛋白质称为 IKAP。由于 IKAP 显然是多个细胞过程所必需的，而 FD 是一种渐进的神经退行性疾病，最近人们投入了大量精力来识别和测试以下化合物：增加 IKAP 表达，希望增加 IKAP 水平能够阻止疾病进展和/或逆转某些疾病表型。然而，由于 FD 具有很强的发育成分，因此尚不清楚增加 IKAP 表达到什么程度可以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。尽管测试了可增加 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，从而确定何时应开始治疗以及治疗成功所需的 IKAP 最佳水平代表着一项艰巨的努力。此外，这种药物可能会产生长期的全身毒性副作用。化合物可能会掩盖其有益作用。使用 Cre-loxP 重组系统，我们生成了一个独特的 FD 小鼠模型，仅概括了大量的疾病表型特征，但也可用于遗传分析随意恢复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，我们建议使用以下方法评估在不同时间点全局恢复 IKAP 表达的效果：他莫昔芬诱导的 Cre 转基因系。完成此申请将揭示旨在提高 IKAP 的 FD 疗法的全部潜力表达水平，指导未来的研究走向补充治疗方法，并允许进一步了解 FD 的潜在机制。