Novel therapeutic strategy for renal fibrosis by targeting RNA-binding protein HuR

靶向RNA结合蛋白HuR的肾纤维化新治疗策略

基本信息

批准号：
10409818
负责人：
yufeng huang
金额：
$ 35.36万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-04 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10409818
关键词：
Adjuvant Therapy Affect Angiotensin II Animal Model Animals Antibodies Antigens Attenuated Binding Proteins Biodistribution Biological Assay Biological Markers Cell Line Cell Survival Cell physiology Cells Chronic Chronic Kidney Failure Clinical Companions DOCA Data Development Diabetic Nephropathy Disease Disease Progression Disease model Disease remission Dose Drug Kinetics End stage renal failure Exhibits Fibrosis Future Genes Genetic Translation Glomerular Mesangial Cell Glomerulonephritis Goals Growth Healthcare Human Hypertension Immune response Immunoprecipitation In Vitro Inflammation Inflammatory Injections Injury Injury to Kidney Innovative Therapy Ischemia Kidney Kidney Diseases Kidney Failure Lead Malignant Neoplasms Maximum Tolerated Dose Mediating Mediator of activation protein Messenger RNA Metabolism Methods Modeling Monitor Nephritis Outcome Patient Care Patient Selection Patients Prevalence Proteins Proteinuria RNA-Binding Proteins Rattus Reaction Renal Tissue Renal function Renal glomerular disease Reperfusion Therapy Ribonucleoproteins Risk Route Safety Schedule Series Testing Therapeutic Therapeutic Effect Tissues Translations Tubular formation Validation base cytokine cytotoxicity experimental study glomerulosclerosis high throughput screening improved in vivo inhibitor kidney cell kidney fibrosis knock-down lead optimization mRNA Stability novel novel therapeutic intervention overexpression response small hairpin RNA small molecule targeted biomarker targeted treatment transcriptome sequencing treatment strategy

项目摘要

Fibrotic renal disease represents a major health care problem because of its prevalence and the fact that available therapies merely slow the progression of renal failure. New innovative therapies to slow or stop the progression to the end-stage renal disease (ESRD) are urgently needed. It has been well established that inflammation is a key factor in the development and progression of renal fibrosis. However, it is impossible to reduce renal inflammatory reaction sufficiently by inhibiting a single inflammatory factor. Very recently, human antigen R (HuR), a mRNA-binding protein governing mRNA stability and translation, has been identified as a key modulator in immune response and inflammation through regulating mRNA stability of cytokines, inflammatory factors, and proteins critical for cell function and survival. Enhanced renal HuR translocation and activation has been observed in varied kidney diseases. Therefore, targeting HuR might provide us with an ideal way to against renal inflammation and thereby controlling renal disease progression. Importantly, we recently identified a specific HuR inhibitor, KH-3, which significantly ameliorated renal function and reduced proteinuria and renal fibrosis in the experimental glomerulonephritis model. Based on our exciting data, we hypothesize that inhibition of HuR function in renal cells with KH-3 will inhibit HuR-targeted genes that are critical for renal inflammation and fibrosis and thereby leading to remission of chronic kidney disease (CKD). To test our hypothesis, we will 1) examine the in vitro anti-fibrotic activity, target validation and mechanism(s) of action of KH-3 in rat and human renal glomerular mesangial cells and tubular cells stimulated by angiotensin II and TGFβ1, two major profibrotic mediators; 2) refine and optimize the dose/schedule, delivery method and off-targeting of KH-3 in vivo in rats with nephritis, compared with normal rats, based on PK/PD and MTD; and 3) Evaluate the therapeutic potential of KH-3 in vivo using animal models with progressive CKD related to glomerulosclerosis or tubulointerstitial fibrosis or both. Successfully carried out, our results will serve as an important basis for translation into the clinical setting with improved potential for patient care for those living with, or at the risk of, progressive CKD.

纤维化肾脏疾病代表了一个主要的医疗保健问题，因为它的患病率和可用疗法仅减慢了肾衰竭的进展。迫切需要新的创新疗法，以减慢或阻止末期肾脏疾病（ESRD）的进展。已经很好地确定感染是肾纤维化发展和发展的关键因素。但是，不可能通过抑制单个炎症因子充分降低肾脏炎症反应。最近，通过调节细胞因子的MRNA稳定性，炎症因子和蛋白质对细胞功能和存活至关重要的MRNA稳定性，人类抗原R（HUR）是一种控制mRNA稳定性和翻译的mRNA结合蛋白，被确定为免疫增强和注射的关键调节剂。在各种肾脏疾病中观察到了增强的肾功能翻译和激活。因此，针对HUR可能会为我们提供防御肾脏感染的理想方式，从而控制肾脏疾病的进展。重要的是，我们最近确定了一种特定的HUR抑制剂KH-3，该抑制剂可显着改善肾功能，并在实验性肾小球肾上腺炎模型中显着改善肾功能和蛋白尿和肾纤维化。基于我们的激动人心的数据，我们假设抑制KH-3肾细胞中HUR功能的抑制作用将抑制针对肾脏感染和纤维化至关重要的HUR靶向基因，从而导致慢性肾脏疾病（CKD）的缓解。为了检验我们的假设，我们将1）检查KH-3在大鼠和人肾肾小球肾小球膜细胞和人血管紧张素II和TGFβ1刺激的基体抗纤维化活性，靶标验证和机制，两个主要的盈利介质。 2）基于PK/PD和MTD，与正常大鼠相比，在患有肾炎大鼠的大鼠体内KH-3在体内的剂量/时间表，递送方法和靶向不靶向； 3）使用与肾小球硬膜病或肺叶骨纤维化相关的进行性CKD的动物模型评估KH-3在体内的治疗潜力。成功进行的结果将成为转化为临床环境的重要基础，并提高了患者护理的潜力或有渐进CKD的风险。