Precision Medicine for the Peripheral Nervous System Disorder Familiar Dysautonomia

周围神经系统疾病（熟悉的自主神经功能障碍）的精准医学

• 批准号: 10392595
• 负责人: Nadja Zeltner
• 金额: $ 7.18万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392595
• 关键词: Actins; Affect; Afferent Neurons; Age; Animal Model; Autonomic nervous system; Binding; Brain; Cadherins; Cell Count; Cell Line; Cells; Chemicals; Childhood; Chinese Traditional Medicine; Crosslinker; Cytoskeleton; DNA Sequence; Defect; Development; Disease; Dysautonomias; Extracellular Matrix; Extracellular Matrix Proteins; Familial Dysautonomia; Familial disease; Frequencies; Functional disorder; Future; Genes; Genetic; Goals; Heart Rate; Human; In Vitro; Kinetics; Knowledge; Laminin; Lead; Light; Longitudinal Studies; Modeling; Modification; Molecular; Mutation; Neurodegenerative Disorders; Neurons; Nociception; Pain; Pathway interactions; Patients; Peripheral Nervous System; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phenotype; Point Mutation; Population; Property; Proteins; Reporting; Research; Research Personnel; Sampling; Sensory; Severities; Severity of illness; Symptoms; Testing; Tissues; Transcription Elongation; Transfer RNA; Vomiting; Work; blood pressure regulation; crosslink; effective therapy; exome sequencing; genipin; human disease; human pluripotent stem cell; improved; induced pluripotent stem cell; insight; novel; pain sensation; precision medicine; stem cell technology; tool

Project summary/Abstract Familial Dysautonomia represents a rare, particularly devastating form of a peripheral nervous system (PNS) disorder. Defective development and degeneration of the sensory and autonomic nervous system in FD patients leads to symptoms including decreased sensitivity to pain and difficulty regulating blood pressure or heart rate. Some FD patients can have very severe symptoms, while others have much milder symptoms. Interestingly, this is the case despite the fact that 99.5% of all patients carry a homozygous mutation in the gene ELP1 (previously IKBKAP). ELP1 protein is involved in transcriptional elongation and tRNA modification, amongst other functions, and the mutation specifically affects PNS tissues. There are no approved drugs for FD available and patients’ symptoms are merely managed. There is a critical need for a deeper understanding of the mechanistic underpinning of FD for the development of precise and effective treatments. To understand why there is this discrepancy of severity in FD, we employed the human pluripotent stem cell (hPSC) technology and successfully recapitulated phenotypes in vitro that captured varying disease severity seen in patients. For example, decreased sensation of pain was captured by the development of decreased numbers of sensory neurons derived from severe FD PSCs. This model further allowed us to identify three potential modifier mutations in LAMB4, KIAA1211 and FAT2, an extra cellular matrix (ECM) protein, actin regulator and cadherin, respectively. These were present in severe FD patients only and were absent in mild patients. Thus, we established the basis for a new paradigm in FD research that FD may consist of two genetically distinct sub-diseases. In preliminary studies, we were able to employ this model to conduct a chemical screen that allowed us to identify a compound called genipin that was able to rescue the severe FD phenotype. Here, we propose to expand on our previous discoveries and define the molecular mechanism behind severe FD. In Aim 1, we aim to understand the molecular mechanism underlying severe FD. In Aim 2, we investigate the mode of action of genipin and how it may aid us in understanding the mechanism of severe FD as well as be developed as a potential future treatment option for FD patients. We believe our studies may enable us to move the field closer toward precision medicine for FD patients and provide deep molecular insights into the understanding of other PNS disorders.

项目概要/摘要 家族性自主神经功能障碍是一种罕见的、特别具有破坏性的周围神经系统 (PNS) 形式 紊乱。 FD患者感觉神经和自主神经系统发育缺陷和退化 导致症状包括对疼痛的敏感性降低以及难以调节血压或心率。 一些 FD 患者可能有非常严重的症状，而另一些患者则有较轻微的症状。有趣的是，这 尽管 99.5% 的患者携带 ELP1 基因纯合突变（之前为 IKBKAP）。 ELP1 蛋白参与转录延伸和 tRNA 修饰等功能， 并且该突变特别影响三七总皂甙组织。目前尚无批准用于 FD 的药物，且患者的情况 症状只是得到控制。迫切需要更深入地了解其机制 FD 的基础是开发精确有效的治疗方法。要理解为什么会有这个 针对 FD 严重程度的差异，我们采用人类多能干细胞 (hPSC) 技术并成功 体外概括的表型捕获了患者中观察到的不同疾病严重程度。例如， 疼痛感的减弱是通过感觉神经元数量的减少来体现的 源自严重的 FD PSC。该模型进一步使我们能够识别三个潜在的修饰突变 LAMB4、KIAA1211 和 FAT2，分别是一种细胞外基质 (ECM) 蛋白、肌动蛋白调节剂和钙粘蛋白。 这些仅存在于严重 FD 患者中，而在轻度患者中不存在。至此，我们建立了基础 FD 研究的新范式是，FD 可能由两种遗传上不同的亚疾病组成。在初步 研究中，我们能够利用这个模型进行化学筛选，使我们能够识别化合物 称为京尼平的药物能够挽救严重的 FD 表型。在这里，我们建议扩展我们之前的 发现并定义了严重 FD 背后的分子机制。在目标 1 中，我们旨在了解 严重FD的分子机制。在目标 2 中，我们研究了京尼平的作用方式以及它如何发挥作用。 可能有助于我们了解严重 FD 的机制并开发为未来潜在的治疗方法 FD 患者的选择。我们相信我们的研究可能使我们能够将该领域推向精准医学 为 FD 患者提供深入的分子见解，以了解其他 PNS 疾病。