Molecular genetics of ANCA glomerulonephritis

本项目探索抗中性粒细胞胞浆自身抗体(ANCA)肾小球肾炎的分子遗传学。本研究的目的是确定ANCA肾炎的允许或改变表达的基因及其控制因素，以阐明ANCA肾炎的病因和治疗。在本项目中，我们观察了ANCA肾炎患者成熟白细胞中蛋白水解酶3(PR3)和髓过氧化物酶(MPO)mRNA的异常表达。ANCA通过以下途径激活中性粒细胞和单核细胞 与这些细胞表面的目标抗原相互作用。了解MPO和PR3基因在活动期ANCA肾炎中的表达机制是研究ANCA肾炎发病机制的关键。特异性目的1假设存在允许PR3和MPO消息异常表达的可识别因素，从而导致活动期ANCA肾炎患者白细胞中靶抗原的过度表达。我们积累了ANCA肾炎和其他自身免疫性疾病患者的转录微阵列数据，并确定了一些关键的基因。使用候选基因，然后是全基因组扫描方法，特定目标2假设存在允许或改变ANCA肾炎表达的基因。这一目的是从转录微阵列研究中合乎逻辑地得出的。利用迭代生物信息学，我们识别了几个与ANCA小血管炎疾病活动相关的基因，其中一些已经用实时RT-PCR证实，还有一些我们正在发现。特定目的3假设，与任何现有的临床可用参数相比，有限数量的白细胞基因的白细胞信使核糖核酸签名将为确定临床疾病的复发和缓解提供更敏感和更具体的策略。我们准备开始一种方法，把候选的“基因”放在棍子上，前瞻性地采样患者的白细胞基因表达，作为临床疾病活动的标志。临床上的紧迫性很大，因为目前还没有包括ANCA滴度在内的疾病活动性的临床标志，可以可靠地回答医生和他们患有ANCA肾炎或任何自身免疫性疾病的患者的关键难题？？也就是，我什么时候可以停止，什么时候需要重新开始救命 危及生命的免疫抑制疗法？“

This Project explores the molecular genetics of anti-neutrophil cytoplasmic autoantibody (ANCA) glomerulonephritis. The objective of this proposal is to identify genes and their controlling factors that are permissive for or modify the expression of ANCA glomerulonephritis for elucidation of the etiology and therapy of this disorder. In the current Program Project, we observed aberrant expression of proteinase 3 (PR3) and myeloperoxidase (MPO) mRNA in mature leukocytes of patients with ANCA glomerulonephritis. ANCA activate neutrophils and monocytes by interacting with their target antigens on the surface of these cells. Understanding the mechanism of MPO and PR3 gene expression in active ANCA glomerulonephritis is a critical key to the disease pathogenesis. Specific Aim 1 hypothesizes that there are identifiable factors permitting aberrant expression of message for PR3 and MPO, resulting in over-expression of target antigens in leukocytes from patients with active ANCA glomerulonephritis. We have accumulated transcriptional microarray data on patients with ANCA glomerulonephritis and other autoimmune diseases, and have identified a number of critically important genes. Using a candidate gene and then a whole genome scan approach, Specific Aim 2 hypothesizes that there are genes permissive for, or that modify the expression of ANCA glomerulonephritis. This aim follows logically from the transcriptional microarray studies. Using iterative bio informatics, we identified several genes that correlate with ANCA small vessel vasculitis disease activity, some of which have been confirmed with real time rtPCR, and we are uncovering still others. Specific Aim 3 hypothesizes that the leukocyte mRNA signatures for a restricted number of leukocyte genes will provide a more sensitive and specific strategy for defining clinical disease relapse and remission than any existing clinically available parameter. We are ready to embark on an approach that places candidate "genes on a stick" to prospectively sample patient leukocyte gene expression as markers of clinical disease activity. The clinical exigency is great, for there is no existing clinical marker of disease activity, including ANCA titers, that reliably answers the critical conundrum for doctors and their patients with ANCA glomerulonephritis, or any autoimmune disease-that is, "When can I stop and when do I need to restart life-saving yet life-threatening immunosuppressive therapy?"