Transition Program in Clinical Research

通过这项研究，我们试图确定TGF-β信号失调促进特应性的机制，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。患有先天性糖基化障碍（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的患者正在积极招募和研究。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，离散免疫途径和糖基化过程中的缺陷正在采用许多技术进行积极研究，包括细胞转染和小分子，siRNA和抗体的途径抑制。为患者提供CDG和单糖和核苷补充剂免疫失调证据的临床方案开放招募，目前正在招募患者。该方案将提供新的见解糖基化的改变可能发挥的作用，特应性的特征如何补充可能会改变免疫反应。

Through this research, we seek to identify the mechanism by which dysregulated TGF-beta signaling promotes 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. 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, defects in discrete immune pathways and in glycosylation processes 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 evidence of immune dysregulation with monosaccharide and nucleoside supplementation is open for enrollment and currently recruiting patients. This protocol will provide novel insights into the role that alterations in glycosylation may play in atopy by characterizing how supplementation may alter immune responses.