DADA2的分子机制研究

DADA2是由于ADA2缺陷导致的遗传病，临床表型为发烧，皮疹，中风，结节性动脉炎。申请人之前的研究发现ADA2 缺陷导致M2巨噬细胞的分化缺陷，产生更多的促炎性巨噬细胞引发血管炎。然而，导致DADA2的炎症信号通路的分子机制仍然不清楚。申请人之前的研究发现TNF抑制剂对控制DADA2病人的血管炎有很好的效果，但是TNF抑制剂的治疗机制并不清楚。本课题的研究目的是解析DADA2的致病和治疗的分子机制。本课题中申请人通过质谱分析，单细胞RNA测序，免疫组化，巨噬细胞分化和ADA2敲除斑马鱼实验等深入研究分子机制。申请人初期的研究显示在DADA2病人中炎性的细胞因子分泌升高，同时DADA2病人在使用TNF抑制剂后巨噬细胞的分化缺陷得到改善， 病人的血管壁内皮细胞也得到修复。申请人将研究DADA2的致病机理和DADA2响应TNF抑制剂的分子机制，开启对ADA2缺陷的致病分子机制研究的全新领域。

Deficiency of Adenosine Deaminase 2 (DADA2) is a recessively inherited disorder caused by a loss of functional ADA2 protein. DADA2 is associated with a broad spectrum of features including fevers, livedoid rashes, recurrent strokes, polyarteritis nodosa, and immunological manifestations. Deficiency of ADA2 has been associated with skewed differentiation towards pro-inflammatory M1 macrophages, which leads individuals with DADA2 to have cycles of exaggerated inflammatory response, and vasculitis. However, the molecular mechanism of the DADA2 in inflammatory signaling pathways is still unknown. TNF inhibition is very successful in preventing vascular crisis in patients and mitigates other systemic and organ-specific features. However, the mechanism of this response remains largely unknown..The aim of this study is to explore the pathophysiology and the underlying mechanisms of TNF inhibitor response in these patients. .We will use Mass spectrometry, single cell transcriptome analysis, immunohistochemistry, cell differentiation experiments and ADA2 knockout Zebrafish to define an inflammatory signature in DADA2 patients and studied their response to TNF inhibitor treatment. .Our primarily experiment data indicated that the increased inflammatory signals and overproduction of cytokines mediated by type I IFN and NF-κB pathways in primary patients’ cells. Treatment with TNF inhibitors led to reduction in inflammation, rescued the skewed differentiation towards the pro-inflammatory M1 macrophage subset and integrity of endothelial cells in blood vessels..Our study will investigate and demonstrate the molecular mechanism of the DADA2 and the cellular mechanism underlying effective treatment with anti-TNF therapies.