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.

总结 中风是美国残疾的主要原因，除了物理治疗外， 这种负担是不存在的。中风后，细胞死亡和神经胶质瘢痕形成导致非- 再生性中风腔被再生性梗塞周围区域包围。我们有兴趣了解 生物工程疗法如何与梗死周围区域的促修复程序协同作用， 促进中风腔中的组织再生，从而改善神经恢复。我们先前已经 设计了一种双重作用的血管生成水凝胶，当注射到中风腔中时，可以减少神经胶质瘢痕形成 并促进血管形成以允许轴突浸润。虽然在中风腔中实现大脑修复是 值得注意的是，这些结果是在神经可塑性未受损的年轻小鼠中取得的。我们相信，要实现这一目标， 技术更接近临床翻译，我们必须能够在更多的情况下显示类似的大脑修复和行为改善。 临床相关的动物模型，如神经可塑性降低的老年小鼠。在本申请中，我们的目标是识别 我们的血管生成水凝胶的作用机制，并优化其配方，并利用这种新的配方， a中风模型具有降低的神经可塑性。该水凝胶由用以下物质官能化的透明质酸组成： 细胞结合整联蛋白，并装载成簇的血管内皮生长因子（VEGF）和肝素 纳米粒子肝素是一种已知的抗炎剂，其潜在地通过破坏炎性细胞而起作用。 中风后巨噬细胞和星形胶质细胞之间的周期。我们将使用实验设计方法， 确定这三种因子（整合素、成簇VEGF和肝素纳米颗粒）的组成， 导致实质性脑修复（目标1），并评估水凝胶组分如何调节促修复 通过分析中风后蛋白质、mRNA和免疫细胞群的时间变化， (Aim 2）。使用改进的配方，我们还将评估血管生成水凝胶促进血管生成的能力。 在更严格的动物模型，特别是老年小鼠治疗神经再生和功能恢复 以脑缺血后即刻和幼年小鼠脑缺血作为可塑性窗口 关闭（目标3）。总的来说，我们的目标是加深我们对生物工程疗法如何协同作用的理解 内源性促再生程序，从而改善斯托克后的行为结果， 难以治疗的病例。