Neurovascualar Regeneration

神经血管再生

• 批准号: 8791687
• 负责人: Karen Kemper Hirschi
• 金额: $ 93.86万
• 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/8791687
• 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; 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; quantitative imaging; 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

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.

描述（由申请人提供）：血管和神经并行发展，其在产后组织中的存活和功能是相互依存的。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系统变性和功能缺陷。中风会影响每年59名成年人中的1个，其中约有500万人是永久残疾人的。 虽然中风的初始损害会产生神经元细胞损失，但该过程迅速发展为其他细胞类型和细胞外基质的丧失，导致空洞的空隙。 我们的初步动物研究在模仿人类中风的模型中表明，单独的神经干细胞（NSC）的移植可能会改善由中风引起的功能缺陷。但是，我们发现没有神经恢复，因为移植细胞仅集成到保留组织结构的区域。 此外，植入的NSC并没有持续，从而限制了维修。 通过生物工程，我们将规避这些当前对细胞移植的局限性，以一种微环境来维持NSC并使它们的传播在体内以及移植后体内能够传播。 我们在先前的研究中为项目奠定了实验基础，在该研究中，我们通过成像和定量分析建立了NSC利基市场的3D模型，并开发了适用于工程于这种微环境的生物材料。 我们还建立了原理证明，表明细胞 - 矩阵构建体的移植是可行的，可以减少病变的大小。 在拟议的研究中，我们将根据我们对大脑中神经发生和血管生成的调节的生物学研究（AIM 1），以及在体外进行顺序测试（AIM 2）和Vivo（AIM 3），在逐渐挑战性和现实的Streoke中，将使Neurer-neurer-infaster comperser compers compers comperer-neurer-closer-neurer-closer-neurer-forser-neurer-neurer-neurer-将继续进行培训。 尽管我们最初的临床靶标将是造成的造成的组织，但获得的见解和制定的策略，我们提出的研究将广泛适用于修复其他神经血管损伤，例如创伤性脑损伤和多发性硬化症。