Strategies in Renal Nanomedicine to Impact Treatment Paradigms in Kidney Disease

项目概述：几十年来，肾脏疾病的治疗模式基本上停滞不前。 然而，干细胞生物学的新技术正在为新的诊断和治疗打开大门。 医疗模式。PI是西北大学的医学博士/博士实习生，其目标是使用F30 NRSA来参加 在肾脏医学和纳米技术领域发展职业利基的第一步。这项培训计划 为有抱负的学术内科医生提供互补的科学和职业发展途径- 科学家将阐明肾脏疾病的机制并开发新的肾脏疗法，这将启动HIS 职业轨迹。具体地说，该项目建议使用新的干细胞技术，这些技术已经在 赞助商的实验室，以产生协调足细胞、内皮细胞的人类多细胞肾脏器官 和上皮细胞形成肾小球、血管和管状室。当肾脏器官形成时 概述了肾脏的发育过程，它们在模拟遗传性疾病(例如， 多囊肾病)已经得到了很好的证实。然而，肾脏类器官对模型的能力获得性 肾脏疾病在很大程度上被忽视了。为了解决这一领域内的不足，这项提议的核心是 研究由导致肾脏损伤和最终疾病的循环因素引起的肾脏病理。至 研究并生成所需的知识，这项研究的广泛假设是3D肾脏 有机化合物可以被利用来开发疾病模型，作为已知的新疗法的试验床 获得性肾损伤的机制(如药物引起的肾毒性)，可用于筛查 获得性肾脏疾病的未知介质。为了研究这一假设并提供概念验证， PI实习生提出了两个目标：Aim 1将有机化合物与一种肾毒性药物孵育，以模拟已知的 肾脏损伤的机制和使用一种新的纳米疗法来测试减轻损伤的能力 由国际和平基金会的赞助商出版。AIM 2通过在体内孵育有机物筛选可疑循环因子 存在来自已建立的银行的患者来源的血浆，该银行来自肾脏患者 功能障碍。本申请中包含的研究策略展示了一种有条不紊且严谨的方法 研究肾脏有机化合物对肾脏医学的影响，并确定有机化合物在多大程度上 可能会微调以重现人类肾脏疾病，并在体外测试新的治疗方法。为了补充 研究计划，并使PI能够开始肾脏纳米医学的职业生涯，这项建议利用 支持肾脏治疗、病理生理学、有机生物学、生物医学等领域的不同导师和资源 工程学和纳米技术。最终，这项NRSA研究和培训计划提供了严格的 计划在肾脏纳米医学领域创造一个新的职业利基，为终身职业生涯揭开 肾脏疾病和用新的治疗药物减轻异常途径。

PROJECT SUMMARY: Treatment paradigms for kidney disease have been largely stagnant for decades. However, new technologies in stem cell biology are opening the doors to novel diagnostic and therapeutic modalities. The PI is an MD/PhD trainee at Northwestern University whose goal is to use this F30 NRSA to take the first steps toward developing a career niche in renal medicine and nanotechnology. This training program combines complementary scientific and career development pathways for the aspiring academic physician- scientist to elucidate mechanisms of kidney disease and develop novel nephrotherapeutics that will initiate his career trajectory. Specifically, this project proposes to use new stem cell technologies, already available in the sponsor's laboratory, to generate human multicellular renal organoids that orchestrate podocytes, endothelial and epithelial cells to form glomerular, vascular and tubular compartments. While renal organoid formation recapitulates the kidney's developmental process, their use in modeling genetic diseases (e.g., such as polycystic kidney disease) has been well established. However, the ability of renal organoids to model acquired diseases of the kidney has been largely ignored. To address this deficit within the field, this proposal centers on investigating renal pathologies due to circulating factors that lead to kidney injury and ultimately disease. To investigate and generate this needed knowledge, the broad hypothesis of this investigation is that 3D kidney organoids can be harnessed to develop disease models as testbeds for novel therapeutics for known mechanisms of acquired kidney injury (such as drug induced nephrotoxicity) AND may be used to screen for unknown mediators of acquired kidney diseases. To investigate this hypothesis and provide a proof-of-concept, the PI trainee proposes two aims: Aim 1 incubates organoids with a nephrotoxic drug to model a known mechanism of kidney injury and tests the ability to attenuate injury using a novel nanotherapeutic developed and published by the PI's sponsors. Aim 2 screens for a suspected circulating factor by incubating organoids in the presence of patient-derived plasma from an already established bank derived from patients with renal dysfunction. The research strategy contained in this application lays out a methodical and rigorous approach to investigate the impact of kidney organoids on renal medicine and to determine the extent to which organoids may be fine-tuned to recapitulate human kidney disease and test novel therapeutics in vitro. To complement the research program and enable the PI to embark on a career in renal nanomedicine, this proposal leverages the support of diverse mentors and resources in kidney therapeutics, pathophysiology, organoid biology, biomedical engineering, and nanotechnology. Ultimately, this NRSA research and training plan provides for a rigorous program to create a new career niche in renal nanomedicine for a lifelong career uncovering mechanisms of kidney disease and attenuating abnormal pathways with novel therapeutic agents.