Neurovascualar Regeneration

神经血管再生

• 批准号: 8632715
• 负责人: Karen Kemper Hirschi
• 金额: $ 103.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-15 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632715
• 关键词: Acute Brain Injuries; Adult; Affect; Animal Model; Animals; Architecture; Area; Autocrine Communication; Biocompatible Materials; Biological; Biology; Biomedical Engineering; Blood Vessels; Brain; Cell Communication; Cell Survival; Cell Transplantation; Cell Transplants; Cell physiology; Cells; Clinical; Clinical Trials; Commit; Complex; Development; Devices; Disabled Persons; Discipline; Disease; Engineering; Extracellular Matrix; Extracellular Protein; Goals; Grant; Health; Human; Hydrogels; Image; In Situ; In Vitro; Injectable; Injury; Ischemic Stroke; Laboratories; Lesion; Manuscripts; Modeling; Multiple Sclerosis; Mus; Natural regeneration; Nerve; Neuroglia; Neurologic; Neurons; Patients; Physiological; Process; Property; Rattus; Regulation; Research; Role; Stem cells; Stroke; Structure of thyroid parafollicular cell; System; Testing; Tissues; Transplantation; Traumatic Brain Injury; Work; angiogenesis; base; bioimaging; body system; cell type; data sharing; design; human disease; improved; in vitro testing; in vivo; in vivo regeneration; injured; insight; member; nerve stem cell; neurogenesis; novel strategies; paracrine; postnatal; programs; public health relevance; quantum; regenerative; regenerative therapy; relating to nervous system; repaired; response; restoration; self-renewal; stem cell biology; stem cell niche; subventricular zone; three-dimensional modeling; tissue repair; tool

Blood vessels and nerves develop in parallel and their survival and function in postnatal tissues are interdependent; thus, when one system is damaged, the other degenerates. Ischemic stroke is one example in which vascular damage leads to neurological degeneration and functional deficits; stroke affects 1 in 59 adults annually of whom ~5 million are permanently disabled. While the initial damage from stroke produces neuronal cell loss, the process quickly evolves into loss of other cell types and extracellular matrix, resulting in a cavitational void. Our preliminary animal studies, in a model that mimics human stroke, suggest that transplantation of neural stem cells (NSC) alone may ameliorate functional deficits caused by stroke; however, we found no neural restoration since transplanted cells integrated only into areas that retained tissue architecture. Moreover, engrafted NSC did not persist, limiting repair. We will circumvent these current limitations of cell transplantation by bioengineering a microenvironment that will sustain NSC and enable their propagation ex vivo, as well as in vivo upon transplantation. We laid the experimental groundwork for our project in previous studies in which we established a 3D model of the NSC niche via imaging and quantitative analysis, and developed biomaterials suitable for engineering this microenvironment ex vivo. We also established proof of principle that transplantation of cell-matrix constructs into stroke models is feasible and reduces lesion size. In the proposed studies, we will continue to optimize the design of our engineered niches based on our biological studies of the regulation of neurogenesis and angiogenesis in the brain (Aim 1), and by sequential testing in vitro (Aim 2) and in vivo (Aim 3) in progressively more challenging and realistic models of stroke, which will enable us to move closer to developing neuro- vascular regenerative therapies for human patients. Although our initial clinical target will be stroke-injured tissues, the insights gained, and strategies developed, from our proposed studies will be broadly applicable to repair of other neurovascular injuries such as traumatic brain injury and multiple sclerosis.

血管和神经平行发育，它们的生存和功能在 产后组织是相互依赖的；因此，当一个系统损坏时，另一个系统 退化。缺血性中风是血管损伤导致的一个例子 神经退行性变和功能缺陷；每年每 59 名成年人中就有 1 人患有中风 约有 500 万人永久残疾。虽然中风造成的最初损害 产生神经元细胞损失，该过程很快演变成其他细胞类型的损失，并且 细胞外基质，导致空化空隙。我们的初步动物研究 模拟人类中风的模型表明神经干细胞（NSC）移植 单独使用可以改善中风引起的功能缺陷；然而，我们发现没有神经 由于移植细胞仅整合到保留组织的区域，因此恢复 建筑学。此外，植入的 NSC 无法持续​​存在，从而限制了修复。我们将规避 目前通过生物工程微环境进行细胞移植的局限性 这将维持 NSC 并使其能够在离体和体内繁殖 移植。我们在之前的研究中为我们的项目奠定了实验基础 我们通过成像和定量建立了 NSC 生态位的 3D 模型 分析，并开发了适合工程化这种微环境的生物材料 体内。我们还建立了细胞基质结构移植的原理证明 转化为中风模型是可行的，并且可以减小病变大小。在拟议的研究中，我们将 根据我们的生物学研究继续优化我们的工程利基设计 大脑中神经发生和血管生成的调节（目标 1），以及 体外（目标 2）和体内（目标 3）的连续测试逐渐变得更具挑战性 和真实的中风模型，这将使​​我们更接近开发神经系统 针对人类患者的血管再生疗法。尽管我们最初的临床目标是 中风损伤的组织，从我们获得的见解和制定的策略 拟议的研究将广泛适用于修复其他神经血管损伤，例如 如创伤性脑损伤和多发性硬化症。