Precision Medicine for the Peripheral Nervous System Disorder Familiar Dysautonomia

项目摘要/摘要 家族性自主神经障碍是一种罕见的，尤其是毁灭性的外周神经系统(PNS)形式 无序。FD患者感觉和自主神经系统发育及变性的研究 导致的症状包括对疼痛的敏感度降低以及难以调节血压或心率。 一些FD患者可能会有非常严重的症状，而另一些患者的症状要轻得多。有趣的是，这 尽管99.5%的患者携带ELP1基因的纯合子突变(以前 IKBKAP)。ELP1蛋白参与转录延长和tRNA修饰等功能， 而且这种突变会专门影响PNS组织。目前还没有批准的治疗FD的药物，而且患者的 症状只是得到了控制。迫切需要更深入地理解这一机制 为开发精确和有效的治疗方法而支持FD。为了理解为什么会有这样的情况 由于FD的严重程度不同，我们应用了人类多能干细胞(HPSC)技术，并成功地 概述了在体外的表型，捕捉到了在患者中看到的不同的疾病严重程度。例如, 痛觉的减少表现为感觉神经元数量的减少。 源于严重的FD PSCs。这个模型进一步允许我们确定三个潜在的修饰物突变 LAMB4、KIAA1211和FAT2，分别是细胞外基质(ECM)蛋白、肌动蛋白调节因子和钙粘蛋白。 这些仅在重度FD患者中存在，而在轻度患者中缺失。因此，我们奠定了基础 对于FD研究中的一种新范式，FD可能由两种不同的基因亚型疾病组成。在预赛中 研究表明，我们能够利用这个模型进行化学筛选，从而识别出一种化合物 一种名为genipin的药物，能够挽救严重的FD表型。在这里，我们建议在以前的基础上进行扩展 发现并确定严重FD背后的分子机制。在目标1中，我们的目标是了解 重度FD的分子机制。在目标2中，我们研究了京尼平的作用模式及其如何 可能有助于我们了解重度FD的发病机制，并可作为一种潜在的未来治疗方法 FD患者的选择。我们相信，我们的研究可能使我们更接近精准医学领域。 并为理解其他PNS疾病提供了深入的分子洞察力。

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.