A new therapeutic approach against kidney damage in LN and COVID-19

狼疮性肾炎（LN）和2019年冠状病毒病（COVID-19）都表现出骨髓细胞功能障碍， 导致信号改变，从而导致组织损伤，例如肾损伤。高达50%的LN患者 据报道，25%的慢性肾脏病（CKD）患者和25%的COVID-19患者经历了急性肾损伤 (AKI)导致长期损伤和功能丧失（42，43，63）。髓样细胞功能障碍导致 促炎性细胞因子（IL-6、IL-1b、TNF-α），其已显示通过刺激 免疫细胞浸润和细胞死亡（60 - 62）。这两种疾病都有明显的增加循环可溶性 尿激酶纤溶酶原激活受体（suPAR），其已被归因于AKI和CKD（39、54、55）。 虽然在COVID-19中已经注意到功能障碍，但没有确凿的证据表明这种疾病和 器官损伤是由骨髓细胞驱动的。目前，没有有效的治疗策略来减少肾功能衰竭。 这些疾病的损害，尽管越来越多的关注导致长期肾功能障碍。分子 TLR信号传导与suPAR表达和分泌的联系机制尚不清楚。我们小组发现 失活的CD11b与LN密切相关。CD11b是CD11b/CD18整合素的α链， 对骨髓细胞的影响进一步的研究显示，CD11b活化抑制TLR信号传导， 体内促炎细胞因子分泌。此外，来自转基因小鼠的CD11b敲入骨髓细胞， 在TLR刺激后，体内suPAR分泌减少 配体。我们实验室开发的白细胞粘附素-1（LA1）对CD11b的药理学激活可降低suPAR 分泌物迄今为止的研究表明，suPAR表达是TLR激活的下游，因此， TLR信号转导是一种潜在的新的治疗肾损伤的方法。我们假设CD11b 通过CD11b激动剂LA1激活，将抑制TLR信号传导，减少suPAR和促炎性因子， 细胞因子水平，从而减少患者的肾损伤。一个多学科的方法将被用来测试这一点 假设通过流动的具体目标：1。评估炎症反应和CD 11b在LN和 COVID-19; 2.）定义suPAR表达背后的分子机制，以及3.）确定brigatinib的疗效 LA1作为这些疾病背景下肾脏疾病的潜在治疗药物。为了达到这个项目的范围， 将进行体内模型、细胞培养、分子生物学和流式细胞术方面的广泛培训。扩大我 培训，几个资源可供我在拉什大学研究生院，如倡议， 最大化学生发展计划和几个研究核心。在博士的出色指导下。 Vineet Gupta，以及杰出的合作者Jochen雷泽博士，Sanja Sever博士，Paul博士 Sanders和Susan Quaggin博士认为，该项目有可能提供出色的培训，影响该领域， 为新疗法的发展打开了大门。总而言之，这个项目将调查是什么推动了 LN和COVID-19，同时评估影响肾损伤机制的治疗方法。

Lupus nephritis (LN) and coronavirus disease 2019 (COVID-19) both display myeloid cell dysfunction which can lead to altered signaling resulting in tissue damage, such as kidney injury. Up to 50% of LN patients develop chronic kidney disease (CKD) and 25% of COVID-19 patients are reported to experience acute kidney injury (AKI) leading to long-term injury and loss of function (42,43,63). Myeloid cell dysfunction leads to secretion of proinflammatory cytokines (IL-6, IL-1b, TNF-a) which have been shown to promote kidney damage by stimulating immune cell infiltration and cell death (60-62). Both diseases have notable increase in circulating soluble urokinase plasminogen activating receptor (suPAR), which have been attributed to both AKI and CKD (39,54,55). While dysfunction has been noted in COVID-19, there is no conclusive evidence on whether this disease and organ injury is myeloid cell-driven. Currently, there are no effective therapeutic strategies to reduce kidney damage in these diseases despite growing concern for resulting long-term kidney dysfunction. The molecular mechanism(s) linking TLR signaling with suPAR expression and secretion is unknown. Our group discovered that deactivated CD11b was highly implicated in LN. CD11b is the alpha chain of the CD11b/CD18 integrin found on myeloid cells. Further investigation displayed that CD11b activation suppressed TLR signaling and reduced proinflammatory cytokine secretion in vivo. Furthermore, CD11b knock-in myeloid cells, from transgenic mice that express functionally active CD11b globally, had reduced suPAR secretion in vivo after stimulation with TLR ligands. Pharmacologic activation of CD11b by leukadherin-1 (LA1), developed in our lab, reduced suPAR secretion. Research so far hints that suPAR expression is downstream of TLR activation, thus, suppression of TLR signaling is a potential novel therapeutic approach against kidney injury. We hypothesize that CD11b activation, through CD11b agonist, LA1, will suppress TLR signaling, decreasing suPAR and proinflammatory cytokine levels, resulting in less kidney damage in patients. A multidisciplinary approach will be used to test this hypothesis through the flowing specific aims: 1.) Assess the inflammatory response and role of CD11b in LN and COVID-19; 2.) Define the molecular mechanism behind suPAR expression, and 3.) Determine the efficacy of LA1 as a potential therapeutic for kidney disease in these disease contexts. To achieve the scope of this project, extensive training in in vivo models, cell culture, molecular biology, and flow cytometry will occur. To expand my training, several resources are available to me at Rush University Graduate College, such as the Initiative to Maximize Student Development program and several research cores. Under the excellent mentorship of Dr. Vineet Gupta, and with the input of distinguished collaborators, Dr. Jochen Reiser, Dr. Sanja Sever, Dr. Paul Sanders, and Dr. Susan Quaggin, this project has the potential to provide excellent training, impact the field and open the doorway to development of novel therapeutics. To summarize, this project will investigate what drives LN and COVID-19 while evaluating therapeutics impacting the mechanisms behind kidney damage.