Axl receptor tyrosine kinase, a potential therapeutic target in glomerulonephritis

Axl 受体酪氨酸激酶，肾小球肾炎的潜在治疗靶点

• 批准号: 9901516
• 负责人: Wen-Hai Shao
• 金额: $ 23.56万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901516
• 关键词: Achievement; Affect; Antibodies; Antigen-Antibody Complex; Apoptosis; Apoptotic; Autoantibodies; Autoimmune Diseases; Autoimmunity; Binding; Cell Proliferation; Cell Survival; Cells; Cessation of life; Complication; Data; Death Rate; Development; Disease; Disease Progression; Epidermal Growth Factor Receptor; FRAP1 gene; Family; Genetic Transcription; Glomerular Mesangial Cell; Glomerular basement membrane antibody; Glomerulonephritis; Human; Hypertrophy; Inflammation; Inflammatory; Interleukin-6; Investments; Kidney; Kidney Diseases; Kidney Failure; Laboratories; Lead; Lupus; Lupus Nephritis; Mediating; Membrane; MicroRNAs; Modeling; Molecular; Mus; Nephritis; Onset of illness; Organ; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Production; Protein Tyrosine Kinase; Proteinuria; Receptor Protein-Tyrosine Kinases; Regulation; Renal glomerular disease; Role; STAT3 gene; Severities; Signal Pathway; Signal Transduction; Signaling Molecule; Systemic Lupus Erythematosus; Testing; Tubular formation; Untranslated Regions; Up-Regulation; angiogenesis; axl receptor tyrosine kinase; base; cell motility; chemokine; cytokine; experience; experimental study; inhibitor/antagonist; mTOR Signaling Pathway; mesangial cell; mouse model; prevent; small molecule inhibitor; therapeutic target; therapy outcome; tool; transcription factor; treatment effect

Nephritis is a serious complication of lupus and can progress to end-stage kidney failure in patients with active disease. The experiments in this proposal will attempt to increase our understanding the role of Axl receptor tyrosine kinase in regulating kidney inflammation and pathogenesis. Our preliminary data demonstrate that Axl contributes to anti-glomerular base membrane (GBM) antibody-induced nephritis by promoting glomerular mesangial cell survival and proliferation. We have shown that Axl-deficient mice are protected against anti-GBM nephritis and that treatment of mice with R428, a specific small molecule inhibitor of Axl signaling, decreases proteinuria and increases survival in mice with this disease. Based on these observations, we will now investigate the regulation of Axl expression by renal mesangial cells, identify the mechanisms by which Axl signaling promotes the pathogenesis of glomerulonephritis, and determine whether treatment with R428 has a general ability to suppress glomerular disease in mouse models of lupus nephritis. Our studies will be guided by three hypotheses: (1) Axl expression by renal mesangial and tubular cells is upregulated by inflammatory cytokines that act through at least 2 mechanisms: (a) transcription factor binding of the Axl 5'- UTRs; and (b) IL-6 activation of Stat3, which increases Axl transcription by decreasing expression of miR-34a. (2) Axl signaling promotes glomerular disease by acting alone or synergistically with MER and EGFR to increase renal mesangial and tubular survival and proliferation through the PI3K/Akt/mTOR pathway. (3) Axl inhibition by R428 will suppress spontaneous and induced murine glomerular disease. These hypotheses will be tested through three specific aims: 1. Will identify the mechanisms that regulate Axl expression in the inflamed kidney. We will investigate two pathways leading to Axl expression in the kidney: 1) Increased IL-6 in the inflamed kidney leads to STAT3 activation, which increases Axl transcription by inhibiting miR34a expression; 2) Axl transcription in the kidney is driven by multiple transcription factors. 2. Will identify the signaling mechanisms by which Axl promotes glomerulonephritis. We will test the hypotheses that: 1) Axl-induced activation of the PI3K and mTOR signaling pathways promotes the survival and proliferation of mesangial/tubule cells, respectively. 2) Axl synergistically interacts with Mer or the EGFR pathway to activate target cells and stimulate cytokine secretion. 3. Will determine the ability of R428 to suppress the development of glomerulonephritis and treat established glomerulonephritis. We will determine whether R428 can inhibit disease progression prior to and after disease onset in inducible and spontaneous models of nephritis. !

肾炎是狼疮的严重并发症，可以在患有 活性疾病。该提案中的实验将试图增加我们的理解AXL的作用 受体酪氨酸激酶在调节肾脏炎症和发病机理中。我们的初步数据证明了 该AXL通过促进抗肿瘤碱膜（GBM）抗体诱导的肾炎有助于 肾小球肾小球的存活和增殖。我们已经表明，AXL缺陷小鼠受到保护 针对抗GBM肾炎，并用R428（AXL的特定小分子抑制剂）对小鼠进行治疗 信号传导，降低蛋白尿并增加这种疾病小鼠的存活率。基于这些观察， 现在，我们将研究肾小管细胞对AXL表达的调节，确定通过 哪种AXL信号传导促进了肾小球肾炎的发病机理，并确定是否处理 R428具有抑制狼疮肾炎小鼠模型的肾小球疾病的一般能力。我们的研究将 以三个假设为指导：（1）肾小管和管状细胞的AXL表达被上调 通过至少两种机制起作用的炎性细胞因子：（a）AXL 5'-的转录因子结合 utrs; （b）IL-6激活STAT3，通过降低miR-34a的表达来增加AXL转录。 （2）AXL信号传导通过单独起作用或与MER和EGFR协同作用促进肾小球疾病 通过PI3K/AKT/MTOR途径增加肾小管和管状存活以及增殖。 （3）Axl R428抑制作用将抑制自发和诱发的鼠肾小球疾病。这些假设会 通过三个特定目标进行测试： 1。将确定调节发炎肾脏中AXL表达的机制。我们将调查 两种导致肾脏AXL表达的途径：1）发炎肾脏中的IL-6增加到STAT3 激活，通过抑制miR34a表达来增加AXL转录； 2）肾脏中的AXL转录 由多个转录因子驱动。 2。将确定AXL促进肾小球肾炎的信号传导机制。我们将测试 假设：1）AXL诱导的PI3K和MTOR信号通路的激活促进了生存 分别是肾小球/小管细胞的增殖。 2）AXL协同与MER或EGFR相互作用 激活靶细胞并刺激细胞因子分泌的途径。 3。将确定R428抑制肾小球肾炎并治疗的能力 已建立的肾小球肾炎。我们将确定R428是否可以抑制疾病的进展和 肾炎诱导和自发模型的疾病发作后。 呢