Mechanisms and Treatment of Kidney Fibrosis

肾脏纤维化的机制和治疗

• 批准号: 10660981
• 负责人: MICHAEL I RAUCHMAN
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10660981
• 关键词: Adverse effects; Affect; African American population; Age; Animal Model; Antisense Technology; Arginine; Aspartic Acid; Attenuated; Binding; Blocking Antibodies; Blood Vessels; Cell Separation; Cells; Chronic Kidney Failure; Cicatrix; Clinical Trials; Complex; Cytokine Signaling; Deposition; Diagnosis; Dialysis procedure; Disease; Dose; End stage renal failure; Extracellular Matrix; Family; Fibrosis; Future; Gene Expression Profiling; Genes; Genetic; Glycine; Growth Factor; Healthcare Systems; Human; Impairment; Individual; Injury; Injury to Kidney; Integrin Binding; Integrin Inhibition; Integrin alphaV; Integrins; Ischemia; Kidney; Kidney Diseases; Kidney Failure; Knowledge; Lysine; Mediating; Mediator; Mesenchymal; Mesenchymal Stem Cells; Modeling; Molecular; Morbidity - disease rate; Morphology; Multiple Trauma; Myofibroblast; Organ; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Pericytes; Pharmaceutical Preparations; Physiology; Platelet-Derived Growth Factor beta Receptor; Population; Proliferating; RGD (sequence); Regulation; Renal function; Risk; Role; Safety; Signal Transduction; Source; Testing; Therapeutic; Therapeutic Trials; Tissues; Transforming Growth Factor beta; Transplantation; Veterans; antifibrotic treatment; burden of illness; cardiovascular risk factor; cytokine; effective therapy; end-stage organ failure; extracellular; human subject; improved; inhibitor; injured; insight; kidney dysfunction; kidney fibrosis; mortality; mouse model; mutant; nephrotoxicity; novel; novel strategies; novel therapeutic intervention; peptidomimetics; preclinical study; precursor cell; prevent; receptor; response; response to injury; small molecule; small molecule inhibitor; smoothened signaling pathway; stem cells; stem-like cell; therapeutic target; transcription factor; translational approach; translational study; urinary tract obstruction

Project Summary Chronic kidney disease (CKD) affects ~15% of the U.S. population. Although a broad range of insults initiate kidney injury, fibrosis is a hallmark of all forms of progressive CKD. In spite of advances in delineating pathways that contribute to kidney fibrosis, there are no specific treatments for this serious disorder. TGF-β signaling is a central mediator of fibrosis in multiple tissues making it an attractive therapeutic target. However, because these cytokines have a wide range of roles in human physiology and pathology, the challenge has been to find a therapeutic strategy that is selective for the diseased target tissue to improve efficacy and safety profiles. A promising approach is to disrupt TGF-β activation in the injured tissue. TGF-β is secreted as a latent, inactive complex that is sequestered in high concentrations in the extracellular matrix. A critical step in the regulation of TGF-β signaling is activation of the latent complex by binding of alpha v (αv) integrins to lysine-glycine-aspartic acid (RGD) motifs. In Aim 1 of this proposal, we will determine if a novel small molecule RGD peptidomimetic inhibitor of TGF-β activation will reduce kidney fibrosis in mouse models of nephrotoxicity, ischemia and urinary tract obstruction. Our preliminary studies indicated that this compound is safe and effective and thus a highly promising candidate for future translational studies in patients. Developing effective treatments for kidney disease requires increased knowledge about molecular mechanisms that drive progressive fibrosis of the organ. Myofibroblasts, derived from peri-vascular mesenchymal progenitor cells are the principal source of extracellular matrix deposition in organ fibrosis. However, the cellular and molecular pathways that control the formation of these cells in response to injury are not well understood. In Aim 2, we will investigate the molecular mechanisms by which alpha v (αv) integrins regulate the proliferation and differentiation of myofibroblasts after injury. These pre-clinical studies will advance knowledge about mechanisms of organ fibrosis and have the potential to identify a novel therapeutic strategy to treat chronic kidney disease in veterans.

项目概要 慢性肾病 (CKD) 影响约 15% 的美国人口。尽管受到各种各样的侮辱 引发肾损伤，纤维化是所有形式的进行性 CKD 的标志。尽管在描绘方面取得了进展 导致肾脏纤维化的途径，但对于这种严重疾病没有具体的治疗方法。 TGF-β信号传导是多种组织纤维化的核心介质，使其成为有吸引力的治疗靶点。 然而，由于这些细胞因子在人体生理和病理中具有广泛的作用， 面临的挑战是找到一种选择性的治疗策略来改善患病的靶组织 功效和安全性概况。一种有前景的方法是破坏受损组织中 TGF-β 的激活。转化生长因子-β是 作为潜在的、无活性的复合物分泌，高浓度地隔离在细胞外基质中。一个 TGF-β 信号传导调节的关键步骤是通过结合 α v (αv) 激活潜在复合物 赖氨酸-甘氨酸-天冬氨酸（RGD）基序的整合素。在本提案的目标 1 中，我们将确定小说是否 TGF-β激活的小分子RGD拟肽抑制剂将减少小鼠模型中的肾纤维化 肾毒性、缺血和尿路梗阻。我们的初步研究表明该化合物 安全有效，因此是未来患者转化研究中非常有前途的候选者。 开发肾脏疾病的有效治疗方法需要增加分子知识 驱动器官进行性纤维化的机制。肌成纤维细胞，源自血管周围 间充质祖细胞是器官纤维化中细胞外基质沉积的主要来源。 然而，控制这些细胞响应损伤形成的细胞和分子途径是 不太理解。在目标 2 中，我们将研究 α v (αv) 整合素的分子机制 调节损伤后肌成纤维细胞的增殖和分化。 这些临床前研究将增进对器官纤维化机制的了解，并具有 有可能确定一种治疗退伍军人慢性肾病的新治疗策略。