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: 10533779
• 负责人: Nadja Zeltner
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10533779
• 关键词: Actins; Affect; Afferent Neurons; Age; Animal Model; Autonomic nervous system; Binding; Biological Assay; Brain; Cadherins; Cell Count; Cell Line; Cells; Chemicals; Childhood; Chinese Traditional Medicine; Crosslinker; 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; Investments; Kinetics; Knowledge; Laminin; Modeling; Modification; Molecular; Mutation; Neurodegenerative Disorders; Neurons; Nociceptors; 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.

项目摘要/摘要 家族性动力障碍代表了周围神经系统（PNS）的一种罕见，尤其是毁灭性的形式 紊乱。 FD患者的感觉和自主神经系统的缺陷发展和变性 导致症状，包括降低对疼痛的敏感性和难以调节的血压或心率。 一些FD患者可能患有非常严重的症状，而另一些患者的症状很大。有趣的是，这 是否提出了这样一个事实，即99.5％的患者在基因ELP1中携带纯合突变（以前 ikbkap）。 ELP1蛋白参与转录伸长和tRNA修饰，除其他功能外， 突变特别影响PNS组织。没有可用的FD和患者的批准药物 症状仅受到治疗。迫切需要更深入地了解机械 FD的基础是开发精确和有效治疗的基础。了解为什么会这样 FD中严重程度的差异，我们采用了人类多能干细胞（HPSC）技术并成功地 体外概括的表型捕获了患者中看到的不同疾病严重程度。例如， 通过减少的感觉神经元的发展捕获了疼痛的降低感 源自严重的FD PSC。该模型进一步使我们能够确定三个潜在的修饰符突变 LAMB4，KIAA1211和FAT2，分别是细胞基质（ECM）蛋白，肌动蛋白调节剂和钙粘蛋白。 这些仅存在于严重的FD患者中，而温和的患者不存在。那我们建立了基础 对于FD研究中的新范式，FD可能包括两个遗传上不同的亚疾病。在初步 研究，我们能够采用该模型进行化学屏幕，使我们能够识别化合物 称为Genipin，能够营救严重的FD表型。在这里，我们建议扩展我们以前的 发现并定义了严重FD背后的分子机制。在AIM 1中，我们旨在了解 严重FD的分子机制。在AIM 2中，我们研究了Genipin的作用方式及其如何 可能有助于我们理解严重FD的机制，并可以作为潜在的未来治疗 FD患者的选择。我们认为我们的研究可能使我们能够更靠近精确医学 对于FD患者，并为理解其他PNS疾病的理解提供了深厚的分子见解。