Repairing the Kidney Endothelium via Targeted Extracellular Matrix Modifiers

通过靶向细胞外基质修饰剂修复肾内皮

基本信息

批准号：
10205482
负责人：
JASON A WERTHEIM
金额：
$ 30.7万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10205482
关键词：
ANGPT1 gene Address Animal Model Animals Basement membrane Binding Biocompatible Materials Biology Biomedical Engineering Blood Blood Circulation Blood Vessels Blood capillaries Blood flow Carrying Capacities Cell physiology Chemistry Chronic Disease Chronic Kidney Failure Collagen Type IV Complex Congestive Heart Failure Coronary heart disease Data Deterioration Diagnosis Dialysis procedure Diffuse Disease Disease Progression Disease model End stage renal failure Endothelial Cells Endothelium Environment Extracellular Matrix Failure Foundations Goals Growth Factor Heparin Heparin Binding Growth Factor Homeostasis Human Hypoxia Inflammatory Inherited Injury Investigation K-Series Research Career Programs Kidney Kidney Diseases Kidney Failure Kidney Transplantation Knowledge Lead Legal patent Length Liquid substance Maintenance Mechanics Mediator of activation protein Medicine Methods Modeling Molecular Nanotechnology Nature Nephrology Organ Pathway interactions Peptides Pericytes Permeability Physiology Population Process Protein Engineering Proteins Proteomics Publications Publishing Research Research Personnel Role Science Specificity Standardization Stroke Supporting Cell System Technology Testing Therapeutic Therapeutic Agents Tight Junctions Tissues Transgenic Model Translating Translations Transplantation United States United States National Institutes of Health Universities Urine Vascular Diseases Vascular Endothelial Growth Factors Vascular Endothelium Venous animal model development base biomacromolecule cell type glomerular endothelium human disease improved improved functioning in vivo innovation kidney dysfunction kidney repair kidney vascular structure mesangial cell migration model design mortality multidisciplinary nanomaterials new technology personalized approach podocyte prevent recruit repaired restoration scaffold solute targeted delivery tool vascular injury wasting

项目摘要

PROJECT SUMMARY The renal microvasculature is the convergence point for inflammatory disorders and hypoxic injury that cause endothelial dysregulation and deterioration of the underlying extracellular matrix (ECM). Together, these changes lead to progressive kidney dysfunction and ultimately failure. The regulatory role of the microvasculature in general—and in particular the microvasculature of the kidney—extends beyond its blood carrying capacity, with global implications to total-body homeostasis. Despite development of animal models of renal vascular dysfunction, which are important components of scientific research, translation of therapeutic tools and knowledge from animals to humans is limited by inconsistent linkages between transgenic models of disease and human vascular physiology. New scientific understanding of the renal vasculature microenvironment, its ECM composition, and the interdependency of endothelial cells within it provide information to develop ex vivo models of renal microvasculature. However, bioengineered systems oftentimes oversimplify the complex, interdependent nature of renal endothelial biology and the necessary cross-talk with pericytes and stroma within the microenvironment. Despite new advances in photolithography and additive manufacturing, the tiny length scales typically found within the in vivo microvasculature cannot be replicated and thus fail to adequately recapitulate the renal microenvironment ex vivo. To address this deficiency, our multidisciplinary team developed a bio-replicative renal microvasculature that mimics the scale, ECM make-up and fluid mechanics of the normal kidney. The foundation for the scientific investigation is this vascularized scaffolding system that is supported by our published data demonstrating patent and perfusable arterial and venous circulation (Caralt et al., Am J Transplant, 2015) with strict control of hydrodynamics (Uzarski, et al., Tissue Eng Part C Methods, 2015) that together result in a bio-replicative ‘test rig’. This platform provides unique opportunities to manipulate the ECM microenvironment with new technologies that unlock cellular function. To enable such an investigation, we developed Targetable ECM Modifiers (TEMs), a new biomaterial delivery system based upon our preliminary and published data (Jiang, et al. Biomacromolecules, 2016) demonstrating ability to discriminately target and shuttle bioactive agents to specific ECM sub-components. Our hypothesis is that endothelial repair leading to vascular restoration can be controlled by delivering bioactive materials to the matrix with specificity to influence endothelial cells at ECM interfaces. Our investigation is supported by data showing a 7-fold enrichment of growth factors within ECM scaffolds accessed by TEMs, compared to soluble factors delivered free in solution, leading to maintenance of an ex vivo vascular endothelium for 28 days where none developed in its absence. This investigation is further enabled by a multidisciplinary team of collaborators in bioengineering, nanotechnology, peptide chemistry and nephrology to tailor the ex vivo renal vasculature with a panel of TEMs to develop testing platforms to study disease and therapies to repair renal vascular injury and reverse kidney disease.

项目概要肾脏微血管系统是导致炎症性疾病和缺氧损伤的汇聚点内皮失调和潜在的细胞外基质（ECM）恶化。变化导致进行性肾功能障碍并最终衰竭。微血管的调节作用。一般来说，特别是肾脏的微血管系统，超出了其血液承载能力，尽管肾血管动物模型的发展对全身稳态具有全球影响。功能障碍，这是科学研究、治疗工具转化和从动物到人类的知识因疾病转基因模型之间不一致的联系而受到限制和人体血管生理学对肾血管微环境及其的新的科学认识。 ECM 组成及其内皮细胞的相互依赖性为离体开发提供信息然而，生物工程系统常常过于简单化复杂的、肾内皮生物学的相互依存性质以及与肾内周细胞和基质的必要相互作用尽管光刻和增材制造取得了新的进展，但微小的长度。通常在体内微脉管系统中发现的鳞片无法复制，因此无法充分为了解决这一缺陷，我们的多学科团队开发了离体肾脏微环境。模仿正常肾微脉管系统的规模、ECM 组成和流体力学的生物复制肾微脉管系统科学研究的基础是这种由血管支撑的支架系统。我们发表的数据证明了专利和可灌注的动脉和静脉循环（Caralt 等人，Am J Transplant，2015）并严格控制流体动力学（Uzarski 等人，Tissue Eng Part C 方法，2015）共同形成了一个生物复制“测试装置”，该平台提供了操纵 ECM 的独特机会。具有解锁细胞功能的新技术的微环境为了实现这样的研究，我们开发了靶向 ECM 改性剂 (TEM)，这是一种基于我们初步研究的新型生物材料输送系统并发表的数据（Jiang 等人，Biomacromolecules，2016）证明了区分目标和我们的假设是内皮修复导致了特定的 ECM 子成分。可以通过将生物活性材料输送到基质来控制血管修复，并特异性地影响我们的研究得到了显示生长富集 7 倍的数据的支持。与溶液中免费提供的可溶性因子相比，TEM 访问 ECM 支架内的因子，领先维持离体血管内皮28天，在没有它的情况下，血管内皮不会发育。由生物工程、纳米技术、肽化学和肾病学通过一组 TEM 定制离体肾脉管系统来开发测试研究修复肾血管损伤和逆转肾脏疾病的疾病和疗法的平台。