Harnessing stem cells and synthetic gene circuits to repair glomerular injury

利用干细胞和合成基因电路修复肾小球损伤

• 批准号: 10687570
• 负责人: Samira Musah
• 金额: $ 142.58万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687570
• 关键词: Address; Adult; Affect; Animal Model; Award; Biological; Biology; Blood; Budgets; COVID-19; Cells; Chronic Kidney Failure; Clinical; Development; Diabetes Mellitus; Dialysis procedure; Disease; Disease Outcome; Disease Progression; Drug Side Effects; Economics; End stage renal failure; Endothelium; Engineering; Environmental Risk Factor; Epithelial Cells; Excision; Expenditure; Experimental Models; Glomerular Capillary; Goals; HIV/AIDS; Human; Injury; Injury to Kidney; Kidney; Kidney Diseases; Kidney Transplantation; Knowledge; Malignant Neoplasms; Medicare; Medicine; Modality; Modeling; Molecular; Molecular Target; Natural regeneration; Nephrology; Organ Transplantation; Organ failure; Organoids; Parkinson Disease; Patients; Pharmaceutical Preparations; Physiological; Population; Process; Public Health; Research; Research Project Grants; Risk; Synthetic Genes; Technology; Tissue Microarray; Tissues; Toxin; United States National Institutes of Health; Virus Diseases; Work; blood filtration; cell injury; cell type; cost; functional restoration; genetic risk factor; glomerular function; high reward; high risk; human stem cells; improved; innovation; microphysiology system; novel therapeutic intervention; novel therapeutics; organ on a chip; podocyte; programs; renal damage; repaired; response; social; stem cell biology; stem cells; tissue repair; tool; wasting

More than 15% of U.S. adults suffer from chronic kidney disease (CKD) and end-stage kidney disease (ESKD), which costs more than $81 billion in annual Medicare expenditures (almost double the entire NIH budget). Worldwide, there are more patients with CKD (850 million) than diabetes (422 million), COVID-19 disease (584 million, August 2022), cancer (42 million), HIV/AIDS (36.7 million), and Parkinson’s disease (10 million). Compounding the overwhelming burden of CKD, there are no therapies proven to reverse or even halt CKD progression to ESKD. Currently, the only treatment options for ESKD are dialysis and kidney transplantation. Because survival on dialysis is limited (five to ten years), and access to organ transplantation is insufficient, many patients die while waiting for a kidney transplant. Innovative, high-risk, high-reward approaches, such as those proposed here, are needed to improve kidney disease outcomes. Progress in kidney medicine is limited by the lack of experimental models that can accurately recapitulate human physiological responses. Due to divergent developmental and functional molecular mechanisms, animal models often fail to faithfully replicate human kidney biology and drug responses. To address this significant limitation, research in my lab integrates technologies at the interface of human stem cell biology, organoids and organs-on-chips or tissue-chip microphysiological systems, and cellular reprogramming to help advance molecular-level understanding of kidney disease mechanisms and discover new therapeutic strategies. The most severe forms of kidney disease involve injury and irreversible damage to podocytes -- the terminally differentiated epithelial cells that encase glomerular capillaries and function together with the endothelium to regulate the removal of toxins and waste from the blood. Because podocytes do not replenish themselves naturally, damage to these cells (through drug side effects, viral infections, genetic and environmental risk factors) often progresses to CKD and organ failure. There is an urgent need to develop new tools to ease the social, economic, and clinical burden of kidney disease. This proposal offers strategies to repair and regenerate damaged kidney tissues by leveraging our stem cell-derived kidney models to uncover tunable molecular targets for cell-type-specific sensing and stimulation of tissue repair processes. We will extend these findings to engineer synthetic molecular circuits for autonomous repair of damaged podocytes and glomerular tissues to help restore the kidney’s blood filtration function. Consistent with the goals of the NIH Director’s New Innovator Award program, this proposal presents an unconventional approach to kidney biology and medicine by providing new avenues to repair and regenerate injured kidney tissues with biological relevance to humans. Accomplishing the goals of this study will represent a paradigm shift in research and clinical nephrology, providing opportunities to develop cell-autonomous strategies as new therapeutic modalities for kidney disease. Thus, the risks are justified by the magnitude of potential impact.

超过 15% 的美国成年人患有慢性肾病 (CKD) 和终末期肾病 (ESKD)，每年的医疗保险支出超过 810 亿美元（几乎是整个 NIH 的两倍） 预算）。全球范围内，CKD 患者（8.5 亿）多于糖尿病（4.22 亿）和 COVID-19 患者 疾病（5.84 亿，2022 年 8 月）、癌症（4200 万）、艾滋病毒/艾滋病（3670 万）和帕金森病（10 百万）。没有任何疗法被证明可以逆转甚至停止，这加剧了 CKD 的巨大负担 CKD 进展为 ESKD。目前，ESKD 唯一的治疗选择是透析和肾病 移植。因为透析的生存期有限（五到十年），并且接受器官移植 由于肾移植不足，许多患者在等待肾移植期间死亡。创新、高风险、高回报 需要诸如此处提出的方法来改善肾脏疾病的结果。进展情况 肾脏医学因缺乏能够准确再现人类肾脏的实验模型而受到限制 生理反应。由于发育和功能分子机制的不同，动物 模型通常无法忠实地复制人类肾脏生物学和药物反应。为了解决这个重大问题 局限性，我实验室的研究整合了人类干细胞生物学、类器官的接口技术 器官芯片或组织芯片微生理系统以及细胞重编程以帮助推进 从分子水平了解肾脏疾病机制并发现新的治疗策略。 最严重的肾脏疾病涉及足细胞的损伤和不可逆的损伤 终末分化的上皮细胞包围肾小球毛细血管并与肾小球毛细血管一起发挥功能 内皮细胞调节血液中毒素和废物的清除。因为足细胞不会补充 自然地，对这些细胞的损害（通过药物副作用、病毒感染、遗传和 环境风险因素）通常会进展为 CKD 和器官衰竭。迫切需要开发新的 减轻肾脏疾病的社会、经济和临床负担的工具。该提案提供了以下策略： 利用我们的干细胞衍生肾脏模型来修复和再生受损的肾脏组织 用于细胞类型特异性传感和组织修复过程刺激的可调节分子靶标。我们将 将这些发现扩展到工程合成分子电路以自主修复受损的足细胞 和肾小球组织，帮助恢复肾脏的血液过滤功能。与 NIH 的目标一致 主任新创新者奖计划，该提案提出了一种非常规的肾脏生物学方法 和医学通过生物修复和再生受损肾组织提供新途径 与人类的相关性。实现本研究的目标将代表研究和研究范式的转变 临床肾病学，为开发细胞自主策略作为新的治疗方法提供了机会 肾脏疾病的治疗方法。因此，潜在影响的大小证明了风险的合理性。