The role of cell death in Lupus Nephritis

描述（由申请人提供）：研究狼疮性别差异的努力主要集中在细胞和体液免疫反应上，很少涉及细胞损伤。近年来，细胞死亡被认为是狼疮性肾小球肾炎（GN）的一个基本致病机制。GN是狼疮疾病最具破坏性的影响之一。它是导致长期残疾的主要原因，也是导致发病率和死亡率的主要原因。尽管女性与男性狼疮的比例高达9:1，但GN在男性中更为严重，这表明两性中参与肾脏损害的分子途径必须具有侵略性。我们最近发现，聚（ADP）核糖聚合酶（PARP） 1（一种参与坏死细胞死亡和促炎细胞因子产生的酶）的抑制或缺失，仅保护雄性小鼠免受狼疮GN的侵害，这表明雄性和雌性在免疫复合物沉积下游的细胞损伤途径不同，免疫复合物沉积是肾脏损伤的基本发起者。因此，本应用的目的是研究狼疮GN期间男性和女性诱导组织损伤、坏死细胞死亡和炎症的分子途径。我们认为狼疮GN时细胞死亡是一种积极参与疾病进展的基本肾脏内在致病机制。我们还提出，在GN期间，促炎性坏死死亡和抗炎性凋亡之间存在平衡，当这种平衡向坏死方向发展时，疾病更严重，进展更快。在AIMs I和II中，我们打算在狼疮GN小鼠模型中证明这些途径受两个主要因素的调节：1) PARP-1诱导坏死，增加促炎细胞因子如HMGB -1的释放，调节粘附分子的表达，促进NF - B的原位活化；2)雌激素通过PARP-1的失活，调节粘附分子、细胞因子的表达，诱导凋亡和坏死细胞死亡。由于有两种主要途径导致坏死细胞死亡，parp -1依赖性和受体相互作用蛋白(RIP)-1和-3依赖性，并且由于坏死也发生在女性中，在AIM I和II中，我们还打算确定女性是否有RIP-1/3依赖性坏死的倾向。在第三AIM中，我们将测试人类狼疮性肾炎中坏死细胞死亡途径的相关性。我们将验证肾炎期间释放的HMGB1可能是人类狼疮GN的生物标志物的假设。我们项目的基本原理是，更好地了解男性和女性狼疮GN病理生理中组织损伤的调节途径，将为每个性别提供量身定制的更好的治疗。

DESCRIPTION (provided by applicant): The effort to investigate the gender differences in lupus has been mostly devoted to the cellular and humoral immune responses and much less to the cellular damage. Recently cell death, the ultimate cell damage, has been recognized as a fundamental pathogenic mechanism in lupus glomerulonephritis (GN). GN is among the most devastating effects of lupus disease. It is the leading cause of long-term disability, and ranks high as a cause of morbidity and mortality. Despite the striking 9:1 female to male lupus ratio, GN is more severe in males, suggesting that the molecular pathways in both sexes involved in the renal damage must be as aggressive. We have recently discovered that the inhibition or deletion of poly (ADP) ribose polymerase (PARP) 1, an enzyme involved in necrotic cell death and production of pro-inflammatory cytokines, protects only male mice from lupus GN, demonstrating the principle that males and females employ different pathways of cellular damage downstream the immune complex deposition, a fundamental initiator of renal damage. Therefore the objective of this application is to investigate the molecular pathways that induce tissue damage, necrotic cell death and inflammation in males and females during lupus GN. We propose that cell death during lupus GN is a fundamental renal intrinsic pathogenic mechanism that actively participates to the disease progression. We also propose that during GN there is a balance between the pro-inflammatory necrotic death and the anti-inflammatory apoptosis, and when this balance is toward necrosis the disease is more severe and progresses at a faster pace. In AIMs I and II we intend to demonstrate in mouse models of lupus GN that these pathways are regulated by two major factors: 1) PARP-1, which induces necrosis, increases the release of pro-inflammatory cytokines, such as high molecular group box (HMGB)-1, modulates the expression of adhesion molecules, and facilitates the activation of NF¿B in situ~ and 2) estrogens, which modulate the expression of adhesion molecules, cytokines and the induction of apoptotic versus necrotic cell death via inactivation of PARP-1. Because there are two major pathways that lead to necrotic cell death, PARP-1-dependent and Receptor Interacting Protein (RIP)-1 and -3-dependent, and because necrosis also occurs in females, in AIM I and II we also intend to determine if females have proclivity for RIP-1/3-dependent necrosis. In the third AIM we will test the relevance of necrotic cell death pathways in human lupus nephritis. We will test the hypothesis that HMGB1 released during nephritis might be a biomarker in human lupus GN. The rationale for our project is that a better understanding of the pathways regulating the tissue damage in lupus GN pathophysiologies in males and females will lead to a tailored and better treatment for each gender.