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

基本信息

批准号：
10645227
负责人：
Alan Davidson
金额：
$ 62.83万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10645227
关键词：
Acceleration Acetylation Acute Renal Failure with Renal Papillary Necrosis Affect Biological Assay CSPG6 gene Cell Culture Techniques Cell Cycle Cell Cycle Kinetics Cell Cycle Progression Cell Cycle Regulation Cells Cessation of life Characteristics Chromatin Loop Chronic Kidney Failure Clinical Clinical Trials DNA Damage DNA Repair Data Deacetylation Disease Progression Drug Kinetics Epithelial Cells G1 Phase Generations Genetic study Goals HDAC8 gene Health Health Care Costs Histone Deacetylase Histone Deacetylase Inhibitor Human Hypertension In Vitro Injury Injury to Kidney Kidney Kidney Failure Mammals Mediating Metabolism Mitosis Modeling Mus Organoids Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Study Play Prodrugs Productivity Property Recovery Regulator Genes Role Series Severities Sister Chromatid Stimulus Structure Testing Therapeutic Time Tubular formation Work Zebrafish analog cohesin cohesion design epithelial repair genetic approach improved in vivo inhibitor injured mouse model multidisciplinary novel pharmacologic pharmacophore preclinical development repaired therapeutic target translation to humans

项目摘要

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).

急性肾损伤 (AKI) 是由一系列伤害性刺激引起的异质性疾病， AKI 每年影响美国超过 150 万名患者，最终造成约 100 亿美元的损失。每年全球有 200 万人因 AKI 死亡而付出医疗费用。后果包括新发高血压伴轻度慢性肾病（CKD），尽管如此，目前尚无有效的临床治疗方法。为了解决这个问题，我们有减轻 AKI 损伤严重程度或加速康复的疗法。组建了一支具有斑马鱼、小鼠和人类肾脏专业知识的多学科团队我们的团队之前发现了一种新的化合物 4- AKI 的类器官模型。硫代丁酸苯酯 (PTBA) 作为前药（UPHD25 或 UPHD186） PTBA 抑制组蛋白脱乙酰酶 8 (HDAC8)，从而改善 AKI 后模型的损伤。在粘连蛋白亚基 SMC3（参与姐妹染色单体粘连）去乙酰化中起主要作用以及基因调节染色质环的形成）。体外研究表明 HDAC8。抑制导致 SMC3 持续乙酰化并延迟细胞周期进程，而无需小鼠体内数据表明，PTBA 会增加有丝分裂的细胞比例。 AKI 后 G0/G1 细胞数量减少，G2/M 细胞数量减少。由于 AKI 诱导的 DNA 损伤，在 G2/M 期停滞在促纤维化状态，我们欺负 PTBA 抑制 HDAC8 可通过减慢细胞周期促进 AKI 恢复，从而提供 TEC 有更多的时间来修复 DNA 损伤，从而减少 G2/M 期停滞的可能性。在两个项目中检验这一假设，这两个项目将 (1) 确认 HDAC8 作为以下疾病的治疗靶点：促进 AKI 后的有效修复，(2) 开发效力更高的新型 HDAC8 抑制剂，最终可以进入临床试验的类似药物的特性和功效。协作和互补的团队完全有能力利用以下方面的专业知识来开展这项工作药物化学和化合物优化（Hukriede、Huryn）和 AKI 模型；哺乳动物（de Caestecker）；斑马鱼（Hukriede，Davidson）；类器官（Davidson，Hukriede）。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Podocyte injury at young age causes premature senescence and worsens glomerular aging.

年轻时足细胞损伤会导致早衰并加剧肾小球老化。

DOI：
发表时间：
2024-01-01
期刊：
影响因子：
0
作者：
Veloso Pereira, Beatriz Maria;Zeng, Yuting;Maggiore, Joseph C;Schweickart, Robert Allen;Eng, Diana G;Kaverina, Natalya;McKinzie, Sierra R;Chang, Anthony;Loretz, Carol J;Thieme, Karina;Hukriede, Neil A;Pippin, Jeffrey W;Wessely, Oliver;Shankla
通讯作者：
Shankla

Hyperoxia Increases Kidney Injury During Renal Ischemia and Reperfusion in Mice.

高氧会增加小鼠肾缺血和再灌注期间的肾脏损伤。

DOI：
发表时间：
2023-11-01
期刊：
影响因子：
5.7
作者：
Kimlinger, Melissa J;No, Tom J;Mace, Eric H;Delgado, Rachel D;Lopez, Marcos G;de Caestecker, Mark P;Billings 4th, Frederic T
通讯作者：
Billings 4th, Frederic T

Inhibition of retinoic acid signaling in proximal tubular epithelial cells protects against acute kidney injury.

抑制近端肾小管上皮细胞中的视黄酸信号传导可预防急性肾损伤。

DOI：
发表时间：
2023-10-23
期刊：
影响因子：
8
作者：
Yang, Min;Lopez, Lauren N;Brewer, Maya;Delgado, Rachel;Menshikh, Anna;Clouthier, Kelly;Zhu, Yuantee;Vanichapol, Thitinee;Yang, Haichun;Harris, Raymond C;Gewin, Leslie;Brooks, Craig R;Davidson, Alan J;de Caestecker, Mark
通讯作者：
de Caestecker, Mark