The role of cell death in Lupus Nephritis

描述(申请人提供)：研究狼疮患者性别差异的研究主要集中在细胞和体液免疫反应方面，对细胞损伤的研究相对较少。近年来，细胞死亡被认为是狼疮肾小球肾炎(GN)的基本发病机制。肾炎是狼疮最具破坏性的后果之一。它是导致长期残疾的主要原因，并被列为发病率和死亡率很高的原因。尽管女性狼疮与男性狼疮的比例达到惊人的9：1，但男性的肾小球肾炎更为严重，这表明参与肾脏损害的两性分子通路肯定具有同样的侵袭性。我们最近发现，抑制或缺失多聚(ADP)核糖聚合酶(PARP)1，一种参与坏死性细胞死亡和促炎细胞因子产生的酶，只保护雄性小鼠免受狼疮GN的影响，这表明了雄性和雌性在免疫复合体沉积下游采用不同的细胞损伤途径的原理，免疫复合体沉积是肾脏损伤的基本启动因素。因此，本研究的目的是探讨狼疮性肾炎中导致男性和女性组织损伤、坏死性细胞死亡和炎症的分子途径。我们认为，狼疮性肾炎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，在肾小球肾炎期间，促炎性坏死性死亡和抗炎性细胞凋亡之间存在平衡，当这种平衡趋向于坏死时，疾病更严重，进展更快。在AIMS I和II中，我们打算在狼疮性肾炎小鼠模型中证明这些通路受两个主要因素的调节：1)PARP-1，它诱导坏死，增加促炎细胞因子的释放，如高分子基团盒(HMGB)-1，调节黏附分子的表达，并促进原位激活的NF？B；2)雌激素，调节黏附分子和细胞因子的表达，并通过失活PARP-1诱导细胞的凋亡性和坏死性死亡。由于有两条主要途径导致坏死细胞死亡，PARP-1依赖和受体相互作用蛋白(RIP)-1和-3依赖，而且由于坏死也发生在女性身上，在AIM I和II中，我们还打算确定女性是否有RIP-1/3依赖的坏死倾向。在第三个目的中，我们将测试坏死性细胞死亡途径在人类狼疮性肾炎中的相关性。我们将验证这一假设，即肾炎期间释放的HMGB1可能是人类狼疮性肾炎的生物标记物。我们项目的基本原理是，更好地了解男性和女性狼疮性肾炎病理生理学中调节组织损伤的途径将导致针对每个性别的量身定制和更好的治疗。

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.