Strategies in Renal Nanomedicine to Impact Treatment Paradigms in Kidney Disease

肾脏纳米医学策略影响肾脏疾病的治疗模式

• 批准号: 10241523
• 负责人: Bilal Abdullah Naved
• 金额: $ 4.22万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2024-09-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241523
• 关键词: 3-Dimensional; Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Animal Model; Antibodies; Attenuated; Beds; Biology; Biomedical Engineering; Blood; Blood Vessels; Cell Death; Chronic; Cisplatin; Collaborations; Complement; DNA; Developmental Process; Disease; Disease model; Doctor of Philosophy; Electron Microscopy; End stage renal failure; Endothelial Cells; Epithelial Cells; Failure; Focal Segmental Glomerulosclerosis; Foot Process; Functional disorder; Genetic Diseases; Genetic Models; Goals; Histology; Human; In Vitro; Incubated; Infrastructure; Injury; Injury to Kidney; Investigation; Kidney; Kidney Diseases; Knowledge; Laboratories; Lead; Libraries; Measures; Mediator of activation protein; Medical; Medicare; Medicine; Mentors; Mentorship; Methods; Modality; Modeling; Molecular; Nanotechnology; National Research Service Awards; Nucleic Acid Amplification Tests; Oligonucleotides; Organ; Organogenesis; Organoids; Pathology; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Physicians; Plasma; Pluripotent Stem Cells; Polycystic Kidney Diseases; Program Development; Publishing; Research; Research Training; Resources; Scientist; Signal Transduction; Spherical Nucleic Acids; Surface; TLR4 gene; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissue Engineering; Toll-like receptors; Toxin; Training; Training Programs; Transfection; Translating; Tubular formation; United States National Institutes of Health; Universities; Visualization; base; career; career development; cost; density; educational atmosphere; human disease; innovation; innovative technologies; kidney cell; kidney dysfunction; nanomedicine; nanotherapeutic; nephrotoxicity; new technology; novel; novel diagnostics; novel therapeutics; podocyte; programs; receptor; research and development; stem cell biology; stem cell technology; therapeutic development; therapeutic nanoparticles; tool; trend

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.

项目总结：肾脏疾病的治疗模式在很大程度上已经停滞了几十年。 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。 方式。PI是西北大学的MD/PhD实习生，其目标是使用F30 NRSA进行 在肾脏医学和纳米技术领域发展职业利基的第一步。这个培训项目 为有抱负的学术医生结合了互补的科学和职业发展途径- 科学家阐明肾脏疾病的机制，并开发新的肾脏疗法，将启动他的 职业轨迹。具体而言，该项目建议使用新的干细胞技术， 申办者的实验室，以产生人类多细胞肾类器官，协调足细胞，内皮细胞， 和上皮细胞形成肾小球、血管和肾小管隔室。而肾类器官形成 概括了肾脏的发育过程，它们在模拟遗传疾病中的用途（例如，等 多囊肾病）已经得到很好的证实。然而，肾类器官的建模能力是获得性的。 肾脏疾病在很大程度上被忽视了。为了解决外地的这一不足，本建议的重点是 研究由于循环因素导致的肾损伤和最终疾病的肾脏病理学。到 调查和产生所需的知识，这项调查的广泛假设是3D肾脏 类器官可用于开发疾病模型，作为已知疾病的新型治疗方法的试验台。 获得性肾损伤的机制（如药物诱导的肾毒性），并可用于筛选 获得性肾病的未知介质。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：目标1用肾毒性药物孵育类器官，以模拟已知的 肾损伤的机制，并测试使用开发的新型纳米颗粒减轻损伤的能力， 由PI的赞助商发布。Aim 2通过在细胞中孵育类器官来筛选可疑的循环因子。 存在来自已建立的来源于肾功能不全患者的库存的患者来源血浆 功能障碍本申请中包含的研究策略提出了一种有条不紊和严格的方法， 研究肾脏类器官对肾脏医学的影响，并确定类器官 可以进行微调以重现人类肾脏疾病并在体外测试新的治疗方法。以补充 研究计划，使PI走上肾脏纳米医学的职业生涯，这项建议利用 支持肾脏治疗学、病理生理学、类器官生物学、生物医学 工程和纳米技术。最终，NRSA的研究和培训计划提供了一个严格的 计划在肾脏纳米医学中创造一个新的职业利基，以终身职业揭示肾脏纳米医学的机制。 肾病和用新的治疗剂减弱异常途径。