Therapeutic Optimization of Productive Repair After Acute Kidney Injury

急性肾损伤后生产性修复的治疗优化

• 批准号: 10441896
• 负责人: Alan Davidson
• 金额: $ 5.8万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441896
• 关键词: Acetylation; Acute Renal Failure with Renal Papillary Necrosis; Affect; Biological Assay; CSPG6 gene; Cell Culture Techniques; Cell Cycle; Cell Cycle Kinetics; Cell Cycle Progression; Cells; Cessation of life; Characteristics; Chromatin Loop; Chronic Kidney Failure; Clinical; Clinical Trials; DNA Damage; DNA Repair; Data; Disease Progression; Drug Kinetics; Epithelial Cells; G1 Phase; Generations; Genetic study; Goals; HDAC8 gene; Health; Health Care Costs; Histone Deacetylase; Human; Hypertension; In Vitro; Injury; Injury to Kidney; Kidney; Kidney Failure; Mammals; Mediating; Metabolism; Mitosis; Modeling; Mus; Organoids; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Play; Prodrugs; Property; Recovery; Regulator Genes; Role; Series; Severities; Sister Chromatid; Stimulus; Structure; Testing; Therapeutic; Time; Tubular formation; Work; Zebrafish; analog; base; cohesin; cohesion; design; epithelial repair; genetic approach; improved; in vivo; inhibitor/antagonist; injured; mouse model; multidisciplinary; novel; pharmacophore; preclinical development; repaired; therapeutic target; translation to humans

Acute kidney injury (AKI) is a heterogeneous condition caused by a range of injurious stimuli that affects >1.5 million patients in the US each year. Ultimately, AKI accounts for ~$10 billion in US healthcare costs and results in 2 million deaths annually worldwide. AKI has long-term health consequences ranging from new onset of hypertension with mild chronic kidney disease (CKD), to progressive CKD ultimately leading to kidney failure. Despite this, there are no effective clinical therapies that reduce the severity of injury or accelerate recovery after AKI. To solve this, we have assembled a multidisciplinary team with expertise in zebrafish, mouse, and human kidney organoid models of AKI. Our team previously discovered a novel compound 4- phenylthiobutanoate (PTBA) that when delivered as a prodrug (UPHD25 or UPHD186) ameliorates injury in models after AKI. PTBA inhibits histone deacetylase-8 (HDAC8), which plays a major role in deacetylating the cohesin subunit SMC3 (involved in sister chromatid cohesion and the formation of gene-regulatory chromatin loops). In vitro studies have shown that HDAC8 inhibition leads to sustained SMC3 acetylation and delays cell cycle progression, without compromising mitosis. In vivo mouse data shows that PTBA increases the proportion of cells in G0/G1 and reduces the number of cells in G2/M after AKI. As tubular epithelial cells (TECs) can arrest in a pro-fibrotic state in G2/M due to AKI-induced DNA damage, we hypothesize that PTBA’s inhibition of HDAC8 promotes recovery from AKI by slowing down the cell cycle, giving TECs more time to repair DNA damage and thus reducing the likelihood of arresting in G2/M. We will test this hypothesis in two projects that will (1) Confirm HDAC8 as a therapeutic target for promoting productive repair after AKI, (2) Develop novel HDAC8 inhibitors with improved potency, drug-like properties, and efficacy that can ultimately be taken into clinical trials. Our highly collaborative and complementary team is well placed to conduct this work with expertise in medicinal chemistry and compound optimization (Hukriede, Huryn); and models of AKI in mammals (de Caestecker); zebrafish (Hukriede, Davidson); cell culture and human kidney organoids (Davidson, Hukriede).

急性肾脏损伤（AKI）是由一系列受伤刺激引起的异质疾病 每年在美国影响> 150万患者。最终，AKI在美国占100亿美元 医疗保健费用和导致全球200万人死亡。 AKI长期健康 从轻度慢性肾脏疾病（CKD）的高血压发作（CKD）的后果， 进步的CKD最终导致肾脏衰竭。尽管如此，没有有效的临床 减少AKI后伤害严重程度或加速恢复的疗法。为了解决这个问题，我们有 组建了一个具有斑马鱼，鼠标和人类肾脏专业知识的多学科团队 AKI的器官模型。我们的团队以前发现了一种新颖的化合物4- 苯硫代植物（PTBA），当以前药为前药时（UPHD25或UPHD186） 在AKI之后，可以缓解模型的伤害。 PTBA抑制组蛋白脱乙酰基酶8（HDAC8） 在脱乙酰基化粘着蛋白亚基SMC3中的主要作用（参与姐妹染色单体凝聚力 以及基因调节染色质环的形成）。体外研究表明HDAC8 抑制会导致持续的SMC3乙酰化，并延迟细胞周期的进展，而没有 损害有丝分裂。体内鼠标数据显示，PTBA增加了细胞的比例 G0/G1并减少AKI后G2/M中的细胞数量。由于管状上皮细胞（TEC）可以 由于AKI诱导的DNA损伤，我们以G2/M的促​​纤维状状态被捕，我们假设PTBA的 抑制HDAC8通过减慢细胞周期来促进AKI的恢复，从而提供TECS 更多时间修复DNA损伤，从而减少了在G2/m中捕捉的可能性。我们将 在两个项目中检验该假设，该假设将（1）确认HDAC8作为治疗目标 促进AKI后的生产维修，（2）以提高效力，开发新型的HDAC8抑制剂， 类似药物的特性和有效性，最终可以纳入临床试验。我们的高度 协作和完整的团队非常适合从事这项工作的专业知识 药物化学和化合物优化（Hukriede，Huryn）；和aki的模型 哺乳动物（de caestecker）；斑马鱼（Hukriede，Davidson）；细胞培养和人类肾脏 类器官（戴维森，Hukriede）。