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

针对 LN 和 COVID-19 肾损伤的新治疗方法

• 批准号: 10595512
• 负责人: Veronica Villanueva
• 金额: $ 2.24万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-04 至 2023-04-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10595512
• 关键词: 2019-nCoV; Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; Agonist; COVID-19; COVID-19 patient; Cell Culture Techniques; Cell Death; Cell surface; Cells; Chronic Kidney Failure; Data; Development; Disease; Flow Cytometry; Functional disorder; Genes; Glomerulonephritis; Hospitalization; ITGAM gene; ITGB2 gene; Immune; Immune response; Immunologic Stimulation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Injury to Kidney; Integrins; Interferons; Interleukin-6; Investigation; Kidney; Kidney Diseases; Knock-in; Ligands; Link; Lupus Nephritis; Macrophage; Mediating; Mentorship; Molecular; Molecular Biology; Mutate; Myeloid Cell Activation; Myeloid Cells; Patients; Pharmaceutical Preparations; Plasmids; Plasminogen; Production; Program Development; Receptor Activation; Receptor Signaling; Reporting; Research; Resources; Role; SARS-CoV-2 infection; SARS-CoV-2 spike protein; Signal Induction; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Students; Systemic Lupus Erythematosus; TNF gene; Testing; Therapeutic; Tissues; Toll-like receptors; Training; Transfection; Transgenic Mice; Universities; Urokinase; Virus; cell injury; cohort; college; comorbidity; cytokine; cytokine release syndrome; efficacy evaluation; experience; immune cell infiltrate; immune function; in vivo; in vivo Model; insight; interdisciplinary approach; kidney dysfunction; loss of function; monocyte; mouse model; new therapeutic target; novel therapeutic intervention; novel therapeutics; organ injury; pharmacologic; podocyte; receptor; receptor expression; recruit; renal damage; therapeutically effective

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.

狼疮性肾炎 (LN) 和 2019 年冠状病毒病 (COVID-19) 均表现出骨髓细胞功能障碍，可导致 导致信号改变，导致组织损伤，例如肾损伤。高达 50% 的 LN 患者出现 据报道，慢性肾病 (CKD) 和 25% 的 COVID-19 患者会出现急性肾损伤 (AKI) 导致长期损伤和功能丧失 (42,43,63)。骨髓细胞功能障碍导致分泌 促炎细胞因子（IL-6、IL-1b、TNF-a）已被证明可通过刺激而促进肾脏损伤 免疫细胞浸润和细胞死亡 (60-62)。这两种疾病的循环可溶性物质均显着增加 尿激酶纤溶酶原激活受体 (suPAR)，已归因于 AKI 和 CKD (39,54,55)。 尽管已注意到 COVID-19 存在功能障碍，但尚无确凿证据表明这种疾病是否与 器官损伤是骨髓细胞驱动的。目前尚无有效的治疗策略来减少肾病 尽管人们越来越担心由此导致的长期肾功能障碍，但这些疾病的损害仍然存在。分子 将 TLR 信号转导与 suPAR 表达和分泌联系起来的机制尚不清楚。我们小组发现 失活的 CD11b 与 LN 密切相关。 CD11b 是发现的 CD11b/CD18 整合素的 α 链 对骨髓细胞。进一步研究表明 CD11b 激活抑制 TLR 信号传导并减少 体内促炎细胞因子的分泌。此外，来自转基因小鼠的 CD11b 敲入骨髓细胞 全局表达功能活性 CD11b，在 TLR 刺激后体内 suPAR 分泌减少 配体。我们实验室开发的 leukadherin-1 (LA1) 对 CD11b 的药理激活可降低 suPAR 分泌。迄今为止的研究表明，suPAR 表达是 TLR 激活的下游，因此，抑制 TLR 信号传导是一种潜在的针对肾损伤的新型治疗方法。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 细胞因子水平，从而减少患者的肾脏损伤。将使用多学科方法来测试这一点 通过以下具体目标提出假设：1.) 评估 LN 中的炎症反应和 CD11b 的作用， 新冠肺炎; 2.) 定义 suPAR 表达背后的分子机制，以及 3.) 确定功效 LA1 作为这些疾病背景下肾脏疾病的潜在治疗方法。为了实现该项目的范围， 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。为了扩展我的 培训，拉什大学研究生院为我提供了多种资源，例如倡议 最大化学生发展计划和多个研究核心。在博士的出色指导下 Vineet Gupta 以及杰出合作者 Jochen Reiser 博士、Sanja Sever 博士、Paul 博士的贡献 桑德斯和苏珊·奎金博士认为，该项目有潜力提供出色的培训，影响该领域并 为开发新疗法打开了大门。总而言之，该项目将调查驱动因素 LN 和 COVID-19，同时评估影响肾脏损伤机制的治疗方法。