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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要：数十年来，肾脏疾病的治疗范例在很大程度上停滞不前。但是，干细胞生物学中的新技术正在为新颖的诊断和治疗开辟大门方式。 PI是西北大学的医学博士/博士学位学员，其目标是使用此F30 NRSA进行发展肾脏医学和纳米技术领域的职业生态位的第一步。这个培训计划结合了有抱负的学术医师的互补科学和职业发展途径 - 科学家阐明肾脏疾病的机制并发展出新的肾疗法，以启动他的职业轨迹。具体而言，该项目建议使用新的干细胞技术，该技术已经在赞助商的实验室，生成人类的多细胞肾脏器官，这些细胞策划了足细胞，内皮细胞和上皮细胞形成肾小球，血管和管状室。而肾脏器官形成概括肾脏的发育过程，它们在建模遗传疾病中的使用（例如多囊性肾脏疾病）已建立得很好。但是，肾脏器官建模获得的能力肾脏的疾病在很大程度上被忽略了。为了解决该领域的这种赤字，该提案以研究导致肾脏损伤和最终疾病的循环因素引起的肾脏病理。到调查并生成所需的知识，这项研究的广泛假设是3D肾脏可以利用类器官开发疾病模型，作为已知的新疗法的测试床获得的肾脏损伤机制（例如药物诱导的肾毒性），可用于筛查未知的肾脏疾病介质。为了研究这一假设并提供概念验证， PI受训者提出了两个目标：AIM 1孵化器官与肾毒性药物以建模已知的药物肾脏损伤的机制，并测试使用开发的新型纳米疗法来减轻损伤的能力，由PI的赞助商出版。 AIM 2屏幕可疑通过孵育器官来自肾脏患者的已经建立的银行的患者来源血浆存在功能障碍。本应用程序中包含的研究策略提出了一种有条理而严格的方法研究肾脏器官对肾脏医学的影响，并确定类器官的程度可以微调以概括人类肾脏疾病并在体外测试新的治疗剂。补充研究计划并使PI能够从事肾脏纳米医学的职业，该建议利用了支持肾脏治疗，病理生理学，器官生物学，生物医学的多种导师和资源工程和纳米技术。最终，该NRSA研究和培训计划提供了严格的计划在肾脏纳米医学中创建新的职业生态位，以终生职业生涯发现肾脏疾病和新型治疗剂衰减异常途径。