Transition Program in Clinical Research

该项目始于2014年7月。通过这项研究，我们试图确定TGF-β信号转导失调导致特应性的机制，并发现糖基化紊乱和血清类胰蛋白酶升高如何汇聚在相似的临床表型上。 我们寻求确定和开发新的诊断和治疗目标，临床过敏性疾病以外的罕见单基因疾病。目前正在积极招募和研究先天性糖基化障碍（CDG）和其他表现为与结缔组织异常相关的严重过敏性疾病的单基因综合征患者。为了研究这些患者，开发了一种高通量的基于流动的凝集素结合测定法来定量N-聚糖结合;现在正用于筛选N-聚糖缺陷的综合征人群。使用TGF-β报告细胞系，采用多种技术，包括细胞转染和小分子、siRNA和抗体的途径抑制，对患者血清的途径激活和由于鉴定的突变进行了积极的研究。为CDG和严重过敏患者提供单糖和核苷补充剂的临床方案正处于最后准备阶段。该协议将提供新的洞察力的作用，O-和N-连接的聚糖可能发挥特应性。

This project began July 2014. Through this research we seek to identify the mechanism by which dysregulated TGF-beta signaling results in atopy and discover how disordered glycosylation, and elevations in serum tryptase converge on a similar clinical phenotypes. We seek to identify and develop novel diagnostic and therapeutic targets for clinical allergic disease beyond rare monogenic disorders. Currently patients with Congenital Disorders of Glycosylation (CDGs), and other monogenic syndromes presenting with severe allergic disease in association with connective tissue abnormalities are actively being recruited and studied. A high throughput flow-based lectin binding assay to quantify N-glycan binding has been developed in order to study these patients; this is now being employed to screen syndromic populations for N-glycan defects. Using a TGF-beta reporter cell line, pathway activation with patient sera and due to identified mutations are under active investigation employing a number of techniques including cellular transfection and pathway inhibition with small molecules, siRNAs, and antibodies. A clinical protocol to provide patients with CDGs and severe allergy with monosaccharide and nucleoside supplementation is in the final stages of preparation. This protocol will provide novel insight into the role that O- and N-linked glycans may play in atopy.