Molecular genetics of ANCA glomerulonephritis

本计画探讨抗中性粒细胞胞浆抗体（ANCA）肾小球肾炎的分子遗传学。本研究的目的是鉴定允许或修饰ANCA肾小球肾炎表达的基因及其控制因子，以阐明这种疾病的病因和治疗。本课题观察了ANCA肾炎患者成熟白细胞中蛋白酶3（PR 3）和髓过氧化物酶（MPO）mRNA的异常表达。ANCA激活中性粒细胞和单核细胞， 与这些细胞表面的靶抗原相互作用。了解MPO和PR 3基因在活动性ANCA肾炎中的表达机制是研究ANCA肾炎发病机制的关键。特定目的1假设存在允许PR 3和MPO信息异常表达的可识别因素，导致活动性ANCA肾小球肾炎患者白细胞中靶抗原过度表达。我们已经积累了ANCA肾小球肾炎和其他自身免疫性疾病患者的转录微阵列数据，并确定了一些至关重要的基因。使用候选基因，然后全基因组扫描的方法，具体目标2假设，有基因允许，或修改表达的ANCA肾小球肾炎。这一目标从转录微阵列研究中逻辑地得出。使用迭代生物信息学，我们确定了几个与ANCA小血管炎疾病活动相关的基因，其中一些已经用真实的时间rtPCR证实，我们正在发现其他基因。特定目标3假设，与任何现有的临床可用参数相比，有限数量白细胞基因的白细胞mRNA特征将为定义临床疾病复发和缓解提供更敏感和特异性的策略。我们准备着手一种方法，将候选基因放在一根棍子上，前瞻性地对患者白细胞基因表达进行采样，作为临床疾病活动的标志。临床上的迫切性是巨大的，因为没有现有的疾病活动的临床标志物，包括ANCA滴度，可以可靠地回答医生和他们的ANCA肾小球肾炎或任何自身免疫性疾病患者的关键难题-也就是说，“我什么时候可以停止，什么时候需要重新开始拯救生命 危及生命的免疫抑制治疗"

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?"