Harnessing stem cells and synthetic gene circuits to repair glomerular injury

超过15%的美国成年人患有慢性肾脏病(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)。新冠肺炎称，在全球范围内，慢性肾脏病患者(8.5亿)多于糖尿病患者(4.22亿) 疾病(5.84亿，2022年8月)、癌症(4200万)、艾滋病毒/艾滋病(3670万)和帕金森氏症(10 百万)。使慢性肾脏病的沉重负担雪上加霜的是，没有任何治疗方法被证明可以逆转或甚至停止 CKD进展为ESKD。目前，ESKD的唯一治疗选择是透析和肾脏。 移植。因为透析的存活率有限(五到十年)，而且获得器官移植的机会 是不够的，许多患者在等待肾脏移植时死亡。创新、高风险、高回报 为了改善肾脏疾病的预后，需要采取类似于本文提出的方法。取得的进展 肾脏医学的局限在于缺乏能够准确概括人类的实验模型。 生理反应。由于发育和功能分子机制的不同，动物 模型往往不能忠实地复制人类肾脏的生物学和药物反应。要解决这一重大问题 局限性，我实验室的研究集成了人类干细胞生物学、有机类化合物的接口技术 以及芯片上器官或组织芯片微生理系统，以及细胞重新编程以帮助推进 从分子水平了解肾脏疾病的发病机制，并发现新的治疗策略。 最严重的肾脏疾病包括对足细胞的损伤和不可逆转的损害-- 终末分化的上皮细胞包裹肾小球毛细血管并与 调节血液中毒素和废物的清除的内皮细胞。因为足细胞不会补充 自然地对这些细胞造成损害(通过药物副作用、病毒感染、遗传和 环境风险因素)通常进展为慢性肾脏病和器官衰竭。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 利用我们的干细胞来源的肾脏模型来修复和再生受损的肾脏组织 可调节的分子靶标，用于特定细胞类型的传感和刺激组织修复过程。我们会 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，以帮助恢复肾脏的血液过滤功能。与美国国立卫生研究院的目标一致 主任的新创新者奖计划，这项提议为肾脏生物学提供了一种非传统的方法 通过提供新的途径修复和再生受损的肾脏组织 与人类的关联性。实现这项研究的目标将代表着研究范式的转变和 临床肾病，提供机会开发细胞自主策略作为新的治疗方法 肾脏疾病的治疗方法。因此，根据潜在影响的大小，风险是合理的。

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.