Precision Medicine for the Peripheral Nervous System Disorder Familiar Dysautonomia

项目概要/摘要 家族性自主神经功能障碍是一种罕见的，特别是破坏性的形式的周围神经系统（PNS） disorder.功能性消化不良患者感觉和自主神经系统的发育和变性缺陷 导致的症状包括对疼痛的敏感性降低和难以调节血压或心率。 一些FD患者可能有非常严重的症状，而另一些患者的症状要轻得多。有趣的是， 尽管99.5%的患者携带基因ELP 1的纯合突变（先前 IKBKAP）。ELP 1蛋白参与转录延伸和tRNA修饰，以及其他功能， 并且该突变特别影响PNS组织。目前还没有批准的FD药物可用， 只是控制了症状。迫切需要更深入地了解 为开发精确有效的治疗方法奠定FD基础。为了理解为什么会有这种 FD严重程度的差异，我们采用了人多能干细胞（hPSC）技术，并成功地 概括了体外表型，其捕获了在患者中观察到的不同疾病严重程度。比如说， 感觉神经元数量的减少是痛觉减少的表现 源自严重FD PSC。该模型进一步使我们能够鉴定出三种潜在的修饰突变， LAMB 4、KIAA 1211和FAT 2，分别是细胞外基质（ECM）蛋白、肌动蛋白调节剂和钙粘蛋白。 这些仅存在于重度FD患者中，而在轻度患者中不存在。因此，我们建立了 为FD研究提供了一个新的范式，即FD可能由两种遗传上不同的亚疾病组成。初步 研究中，我们能够利用这个模型进行化学筛选，使我们能够识别一种化合物， 一种叫做京尼平的药物能够挽救严重的FD表型。在这里，我们建议扩大我们以前的 发现和定义严重FD背后的分子机制。在目标1中，我们旨在了解 严重FD的分子机制在目的2中，我们研究京尼平的作用方式以及它如何影响细胞的增殖。 可能有助于我们了解严重FD的机制，并被开发为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能够使该领域更接近精准医学。 为FD患者提供深入的分子见解，以了解其他PNS疾病。

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.