Neurovascualar Regeneration

描述（申请人提供）：血管和神经平行发育，它们在出生后组织中的生存和功能是相互依存的；因此，当一个系统受损时，另一个系统也会退化。缺血性中风是血管损伤导致神经退化和功能缺陷的一个例子；每年每59名成年人中就有1人罹患中风，其中约500万人终身残疾。虽然中风的初始损伤会导致神经元细胞的损失，但这一过程很快演变为其他细胞类型和细胞外基质的损失，导致空化空洞。我们在模拟人类中风的模型中进行的初步动物研究表明，单独移植神经干细胞（NSC）可以改善中风引起的功能缺陷；然而，我们没有发现神经恢复，因为移植的细胞只整合到保留组织结构的区域。此外，移植的NSC不能持续存在，限制了修复。我们将通过生物工程创造一个微环境来维持NSC并使其在体外和移植后在体内繁殖，从而绕过当前细胞移植的这些限制。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分析建立了NSC生态位的3D模型，并开发了适合于体外工程这种微环境的生物材料。我们还建立了原理证明，移植细胞基质构建到中风模型是可行的，并减少了病变的大小。在拟议的研究中，我们将继续优化我们的工程壁龛的设计，基于我们对大脑神经发生和血管生成调节的生物学研究（目标1），并通过体外（目标2）和体内（目标3）在逐渐更具挑战性和现实的中风模型中的顺序测试，这将使我们更接近为人类患者开发神经血管再生疗法。虽然我们最初的临床目标将是中风损伤组织，但从我们提出的研究中获得的见解和开发的策略将广泛适用于其他神经血管损伤的修复，如创伤性脑损伤和多发性硬化症。

DESCRIPTION (provided by applicant): 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 transplantationby 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 int 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.