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致力于细胞和体液免疫反应，而很少涉及细胞损伤。 近年来，狼疮性肾小球肾炎（GN）的主要致病机制之一是细胞死亡，即最终的细胞损伤。GN是狼疮疾病最具破坏性的影响之一。它是长期残疾的主要原因，是发病率和死亡率很高的原因。尽管女性与男性的狼疮比例为惊人的9：1，但GN在男性中更为严重，这表明参与肾损伤的两性分子途径必须具有侵略性。 我们最近发现，抑制或缺失多聚（ADP）核糖聚合酶（PARP）1（一种参与坏死细胞死亡和促炎细胞因子产生的酶）仅保护雄性小鼠免受狼疮GN，这证明了雄性和雌性在免疫复合物沉积下游采用不同的细胞损伤途径的原理，是肾损伤的根本诱因因此，本申请的目的是研究在狼疮GN期间在男性和女性中诱导组织损伤、坏死细胞死亡和炎症的分子途径。我们认为，狼疮肾炎期间的细胞死亡是一种基本的肾脏内在致病机制，积极参与疾病的进展。 我们还提出，在GN期间，促炎性坏死性死亡和抗炎性细胞凋亡之间存在平衡，当这种平衡朝向坏死时，疾病更严重，进展速度更快。在AIM I和II中，我们打算在狼疮GN小鼠模型中证明这些通路受两个主要因素调节：1）PARP-1，其诱导坏死，增加促炎细胞因子的释放，如高分子组蛋白（HMGB）-1，调节粘附分子的表达，并促进NF-κ B的活化。B原位-和2）雌激素，其通过PARP-1的失活调节粘附分子、细胞因子的表达和诱导凋亡与坏死性细胞死亡。 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雌性动物中，因此在AIM I和II中，我们还打算确定雌性动物是否具有RIP-1/3依赖性坏死的倾向。在第三个目的中，我们将测试人类狼疮肾炎中坏死细胞死亡途径的相关性。 我们将检验肾炎过程中释放的HMGB 1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病理生理学中调节组织损伤的途径将为每个性别提供量身定制的更好的治疗。 公共卫生相关性：狼疮在肾脏中具有最具破坏性的并发症，这是发病率和死亡率的主要原因。狼疮肾损害的最重要特征之一是坏死性病变的存在。我们打算证明性激素和性激素在控制坏死病变中起着重要作用，更好地理解这一过程将为靶向坏死的治疗提供依据。

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. PUBLIC HEALTH RELEVANCE: Lupus has its most devastating complication in the kidney, which is a leading cause of morbidity and mortality. One of the most important characteristics of kidney damage in lupus is the presence of necrotic lesions. We intend to demonstrate that sex and sexual hormones play a fundamental role in controlling the necrotic lesions and that a better understanding of this process will provide the rational for a therapy targeting necrosis.