VEGF ligand presentation and therapeutic angiogenesis

VEGF 配体呈递和治疗性血管生成

• 批准号: 10453141
• 负责人: Tatiana Segura
• 金额: $ 0.72万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453141
• 关键词: Acute; Adult; Affect; Animal Model; Anti-Inflammatory Agents; Applications Grants; Astrocytes; Axon; Behavioral; Biocompatible Materials; Biomedical Engineering; Blood flow; Brain; Brain Injuries; Cell Death; Cells; Cellular Infiltration; Cerebral Ischemia; Chronic; Cicatrix; Development; Dose; Endothelial Cells; Engineering; Environment; Ephrins; Experimental Models; Extracellular Matrix; Formulation; Funding; Generations; Goals; Growth Cones; Heparin; Heparin Binding; Hyaluronic Acid; Hydrogels; Image; Immune; Immune response; Impairment; In Situ; Infarction; Infiltration; Inflammation; Inflammatory; Injectable; Injections; Injury; Integrin Binding; Integrins; Interruption; Ischemic Stroke; Lead; Ligands; Link; Liquid substance; Magnetic Resonance Imaging; Messenger RNA; Methodology; Mus; Natural regeneration; Necrosis; Nervous System Physiology; Neuroglia; Neurologic; Neurologic Deficit; Neuronal Plasticity; Neurons; Patients; Physical therapy; Population; Production; Proteins; Recovery; Recovery of Function; Signal Pathway; Signal Transduction; Stroke; Stromal Cell-Derived Factor 1; Survival Rate; Technology; Testing; Therapeutic; Time; Tissues; Vascular Endothelial Growth Factors; Vascularization; aged; angiogenesis; axon growth; axonal sprouting; base; behavioral outcome; brain repair; brain tissue; clinical translation; clinically relevant; crosslink; cytokine; design; disability; disability burden; disabling disease; experimental study; functional improvement; improved; interest; macrophage; nanoparticle; necrotic tissue; neurogenesis; neurological recovery; neurovascular; new therapeutic target; novel therapeutics; post stroke; programs; regenerative; repaired; skin wound; stroke model; stroke patient; stroke therapy; therapeutic angiogenesis; tissue regeneration; tissue repair; transcriptome

Summary Stroke is the leading cause of disability in the US, and, apart from physical therapy, therapeutic options to reduce this burden are non-existent. Following a stroke, cell death and glial scarring leads to the formation of a non- regenerative stroke cavity surrounded by the regenerative peri-infarct region. We are interested in understanding how bioengineered therapeutics can synergize with pro-repair programs active in the peri-infarct region to promote tissue regeneration in the stroke cavity and thereby improve neurological recovery. We have previously engineered a dual-acting angiogenic hydrogel that, when injected into the stroke cavity, can reduce glial scarring and promote vascularization to allow axonal infiltration. Although achieving brain repair in the stroke cavity is remarkable, these results were achieved in young mice with un-impaired neuroplasticity. We believe that to bring this technology closer to clinical translation, we must be able to show similar brain repair and behavioral improvement in more clinically relevant animal models, like aged mice with decreased neuroplasticity. In this application, we aim to identify our angiogenic hydrogel’s mechanism of action and optimize its formulation and to utilize this new formulation in a stroke models with decreased neuroplasticity. The hydrogel is composed of hyaluronic acid functionalized with cell-binding integrins and loaded with clustered vascular endothelial growth factor (VEGF) and heparin nanoparticles. Heparin is a known anti-inflammatory agent that potentially acts by breaking the inflammatory cycle between macrophages and astrocytes following stroke. We will use design of experiment methodology to determine the composition of these three factors (integrins, clustered VEGF, and heparin nanoparticles) that leads to substantial brain repair (Aim 1) and assess how the hydrogel components modulate the pro-repair environment by analyzing temporal changes in proteins, mRNA, and immune cell populations following stroke (Aim 2). Using the improved formulation, we will also evaluate the angiogenic hydrogel’s ability to promote neurological regeneration and functional recovery in more rigorous animal models, specifically aged mice treated immediately following cerebral ischemia and young mice with cerebral ischemia treated as the plasticity window is closing (Aim 3). Overall, we aim to deepen our understanding of how bioengineered therapeutics synergize with endogenous pro-regenerative programs and thereby improve behavioral outcomes following stoke in more difficult-to-treat cases.

概括 中风是美国残疾的主要原因，除了物理疗法外，还可以减少治疗选择 这个伯恩不存在。中风后，细胞死亡和神经胶质疤痕导致形成非 - 再生型腔周围的再生中风腔。我们有兴趣理解 生物工程疗法如何与活跃于侵略性区域的亲修改计划协同作用 促进中风腔中的组织再生，从而改善神经系统恢复。我们以前有 设计了双作用血管生成水凝胶 并促进血管形成以允许轴突浸润。尽管在中风腔中实现大脑修复是 值得注意的是，这些结果是在具有不受影响的神经可塑性的年轻小鼠中实现的。我们相信要带这个 技术更接近临床翻译，我们必须能够显示出类似的大脑修复和行为改善 临床相关的动物模型，例如具有改善神经可塑性的老年小鼠。在此应用程序中，我们旨在确定 我们的血管生成氢的作用机理并优化了其公式，并在 具有改善神经质量的中风模型。水凝胶由用与 细胞结合整合素，并带有簇状血管内皮生长因子（VEGF）和肝素 纳米颗粒。肝素是一种已知的抗炎剂，可能通过破坏炎症而起作用 中风后巨噬细胞和星形胶质细胞之间的循环。我们将使用实验方法设计 确定这三个因素（整合素，聚集的VEGF和肝素纳米颗粒）的组成，它们是 导致大脑修复（AIM 1），并评估水凝胶成分如何调节pro-Repair 通过分析中风后蛋白质，mRNA和免疫细胞种群的暂时变化，环境 （目标2）。使用改进的公式，我们还将评估血管生成氢的促进能力 在更严格的动物模型中，神经系统再生和功能恢复，特别是老化的小鼠 立即在脑缺血和幼体脑缺血后立即被视为可塑性窗口 正在关闭（目标3）。总体而言，我们旨在加深对生物工程治疗如何协同作用的理解 随着内源性促进计划，从而改善了Stoke之后的行为结果 难以治疗的情况。