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.

狼疮肾炎（LN）和冠状病毒疾病2019（Covid-19）均显示髓样细胞功能障碍，可以 导致信号变化导致组织损伤，例如肾脏损伤。多达50％的LN患者发展 据报告 （AKI）导致长期伤害和功能丧失（42,43,63）。髓样细胞功能障碍导致分泌 促炎细胞因子（IL-6，IL-1B，TNF-A）已证明可以通过刺激来促进肾脏损伤 免疫细胞浸润和细胞死亡（60-62）。两种疾病的循环可溶性都显着增加 尿激酶纤溶酶原激活受体（SUPAR）归因于AKI和CKD（39,54,55）。 尽管在Covid-19中已经注意到功能障碍，但尚无关于这种疾病和是否的结论性证据。 器官损伤是髓样细胞驱动的。目前，没有有效的治疗策略来减少肾脏 尽管人们对长期肾功能障碍的长期关注，但这些疾病的损害。分子 将TLR信号与suPAR表达和分泌的机制尚不清楚。我们的小组发现 该停用的CD11b在LN中高度涉及。 CD11b是发现CD11b/CD18整合素的α链 在髓样细胞上。进一步的研究表明，CD11b激活抑制了TLR信号并减少 体内促炎性细胞因子分泌。此外，转基因小鼠的CD11b敲入髓样细胞 全球表达功能上活性的CD11b，用TLR刺激后体内supar分泌降低 配体。 Leukadherin-1（LA1）在我们的实验室中开发的CD11b的药理学激活，减少了Supar 分泌。到目前为止的研究暗示，supar表达是TLR激活的下游，因此，抑制 TLR信号传导是针对肾脏损伤的一种潜在的新型治疗方法。我们假设CD11b 通过CD11b激动剂LA1激活将抑制TLR信号传导，降低Supar和促炎性 细胞因子水平，导致患者肾脏损伤较少。多学科的方法将用于测试 通过流动的特定目的假设：1。）评估CD11b在LN和 新冠肺炎; 2.）定义Supar表达背后的分子机制，3。）确定 在这些疾病情况下，LA1作为肾脏疾病的潜在治疗方法。为了实现该项目的范围， 将对体内模型，细胞培养，分子生物学和流式细胞仪进行广泛的训练。扩大我的 培训，我可以在拉什大学研究生学院提供几种资源，例如 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，以及杰出合作者Jochen Reiser博士，Sanja Sever博士，Paul博士的投入 桑德斯（Sanders）和苏珊·奎金（Susan Quaggin）博士，该项目有可能提供出色的培训，影响该领域和 打开开发新疗法的门口。总而言之，该项目将调查什么驱动器 LN和Covid-19在评估治疗剂时影响肾脏损伤背后的机制。