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.

血管和神经并行发展，其生存和功能 产后组织是相互依存的。因此，当一个系统损坏时，另一个系统 退化。缺血性中风是一个例子，其中血管损伤导致 神经变性和功能缺陷；中风每年59名成年人中有1个 约有500万人是永久残疾的人。而中风的最初损害 产生神经元细胞丧失，该过程迅速发展为其他细胞类型的丧失， 细胞外基质，导致空洞的空隙。我们的初步动物研究 模仿人类中风的模型，表明神经干细胞的移植（NSC） 仅凭中风引起的功能不足可能会减轻；但是，我们发现没有神经 恢复自移植细胞仅集成到保留组织的区域 建筑学。此外，植入的NSC并没有持续，从而限制了维修。我们将绕过 这些当前通过生物工程微环境进行细胞移植的局限 这将维持NSC并使他们的繁殖离体以及体内 移植。我们在先前的研究中为项目奠定了实验基础 在其中我们通过成像和定量建立了NSC利基市场的3D模型 分析并开发了适合工程的生物材料 体内。我们还建立了原理的证据，即细胞矩阵构建体的移植 进入中风模型是可行的，可降低病变的大小。在拟议的研究中，我们将 继续根据我们的生物学研究来优化我们工程生态位的设计 大脑中神经发生和血管生成的调节（AIM 1），以及 在体外进行顺序测试（AIM 2）和体内（AIM 3）逐渐具有挑战性 和中风的现实模型，这将使​​我们能够更加接近发展神经 人类患者的血管再生疗法。尽管我们最初的临床目标将 是陷入困境的组织，从我们的 拟议的研究将广泛适用于修复其他神经血管损伤 作为脑外伤和多发性硬化症。