Interplay between the host milieu and human neural stem cells in stroke repair

宿主环境和人类神经干细胞在中风修复中的相互作用

基本信息

批准号：
7664388
负责人：
GARY K STEINBERG
金额：
$ 39.71万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7664388
关键词：
Address Adult Affect American Animal Model Apoptotic Behavioral Biological Assay Biological Models Biology Blood Cells Bone Marrow Cells Brain Brain Injuries Bromodeoxyuridine Cell Line Cell Therapy Cell Transplantation Cell Transplants Cell physiology Cells Cerebral Ischemia Cessation of life Clinic Clinical Clinical Trials Communication Confocal Microscopy Deoxyuridine Disease Embryo Event FDA approved Future Goals Golgi Apparatus Graft Survival Human Huntington Disease Image Imaging Techniques Immunohistochemistry Infarction Inflammatory Inflammatory Response Integration Host Factors Ischemia Knowledge Label Lesion Link Location Lysosomal Storage Diseases Measures Methods Modeling Molecular Molecular Probes Monitor Motor Mus Nervous System Physiology Neuroepithelial Cells Neurons Outcome Parkinson Disease Patient observation Patients Principal Investigator Process Property Rattus Recovery Recovery of Function Relative (related person)Research Research Personnel Resolution Rodent Rodent Model Role Signal Transduction Spielmeyer-Vogt Disease Spinal cord injury Staining method Stains Stem cell transplant Stem cells Stroke Stromal Cell-Derived Factor 1 Surveys Techniques Testing Therapeutic Therapeutic Uses Time Transplantation Umbilical Cord Blood Vascular Endothelial Growth Factors Work angiogenesis axonal sprouting base behavior test cell type chemokine disability experience functional outcomes genetic manipulation immortalized cell improved in vivo indexing infancy kidney cell migration molecular imaging neovascularization nerve stem cell nervous system disorder neurogenesis neuron loss overexpression post stroke progenitor programs public health relevance relating to nervous system repaired research study stem stem cell biology stroke recovery stroke therapy success synaptogenesis tomography tool

项目摘要

DESCRIPTION (provided by applicant): Stroke is the number one cause of disability among Americans each year. Currently there is no therapy to cure stroke patients except the thrombolytic treatments, which have limited use. Our long-term goal is to promote functional recovery from stroke using human neural progenitor cells (hNPCs) as a potential therapy. We and others have shown that neural stem/progenitor in some cases can improve neurological function in rodents. However, transplant viability and functional outcome vary widely across studies. Our overall hypothesis is that hNPCs facilitate long-term functional by enhancing endogenous repair mechanisms through secretion of trophic factors. Including a focus on the trophic factors gives a mechanistic understanding of how transplanted stems cells augment endogenous repair processes. Importantly, we do not believe that the cells enhance recovery integrating into the host brain circuitry. In Specific Aim 1, we determine the effect of the transplanted cells on several endogenous repair mechanisms as well as the trophic factors expressed by the hNPCs in vivo over time, and then correlate these phenomena with functional recovery. We then test specific factors by manipulating their expression levels in hNPCs before transplantation. In Specific Aim 2, we determine the host microenvironment that is most conducive to cell-induced repair by varying the timing of transplantation post- stroke, with the goal of finding the optimal time to transplant. We also test the interplay between the host microenvironment and hNPCs by surveying host factors that are affected by hNPCs and also modifying the hNPCs' sensitivity to signals for migration and survival from the host's microenvironment. Together these aims will help identify the optimal time to transplant human neural progenitor cells after stroke and link successful cell therapy with critical molecular and cellular mechanisms that underlie endogenous repair after stroke. Graft survival and biology, and its effect on host repair mechanisms, will be assessed using immunohistochemistry. Functional recovery will be examined using behavioral tests. Our expertise in stroke research and cellular therapies (Kelly, 2004), neural stem cell biology and culture methods (Palmer, 2001), synaptogenesis (Christopherson, 2005), imaging (Micheva, 2007) and genetic manipulation of hNPCs (Suzuki, 2007) provide an excellent opportunity to develop a cross-disciplinary effort to study cell transplants for brain injury at Stanford. PUBLIC HEALTH RELEVANCE: Stroke is the number one cause of disability among Americans each year, and there are limited therapeutic treatments that can be offered. Our long-term goal is to promote functional recovery from stroke using human neural progenitor cells (NPCs) as a potential therapy. In this proposal we seek to understand how the NPCs augment the brain's natural repair processes after stroke so that we can enhance these properties in the future.

描述（由申请人提供）：中风是美国人每年残疾的第一原因。目前尚无治愈中风患者的治疗，除了使用有限的溶栓治疗。我们的长期目标是使用人类神经祖细胞（HNPC）作为一种潜在疗法促进中风的功能恢复。我们和其他人表明，在某些情况下，神经茎/祖细胞可以改善啮齿动物的神经功能。但是，在研究中，移植生存力和功能结果差异很大。我们的总体假设是，HNPC通过通过营养因素的分泌来增强内源性修复机制来促进长期功能。包括对营养因子的关注可以使机械理解移植的茎细胞增强内源性修复过程。重要的是，我们不认为细胞会增强整合到宿主脑电路中的恢复。在特定的目标1中，我们确定了移植细胞对多种内源修复机制的影响，以及随着时间的流逝，HNPC在体内表达的营养因子，然后将这些现象与功能恢复相关联。然后，我们通过在移植前操纵其在HNPC中的表达水平来测试特定因素。在特定的目标2中，我们确定了宿主微环境，该环境最有利于细胞诱导的修复，通过改变中风后移植的时间，目的是找到最佳的移植时间。我们还通过测量受HNPC影响的宿主因子，并改变HNPC对寄主微环境迁移和存活的信号的敏感性，测试宿主微环境与HNPC之间的相互作用。这些目标将有助于确定中风后移植人神经祖细胞的最佳时间，并将成功的细胞疗法与中风后内源性修复的关键分子和细胞机制联系起来。将使用免疫组织化学评估移植物的生存和生物学及其对宿主修复机制的影响。功能恢复将使用行为测试检查。我们在中风研究和细胞疗法方面的专业知识（Kelly，2004年），神经干细胞生物学和培养方法（Palmer，2001），突触发生（Christopherson，2005），Imaging（Micheva，2007年）和HNPC的遗传操纵（Suzuki，2007）（Suzuki，2007）（Suzuki，2007）提供了跨越细胞施加跨越细胞训练的绝佳机会。公共卫生相关性：中风是美国人每年造成残疾的第一大原因，并且可以提供治疗方法有限。我们的长期目标是使用人类神经祖细胞（NPC）作为一种潜在疗法促进中风的功能恢复。在此提案中，我们试图了解NPC在中风后如何增强大脑的自然修复过程，以便我们将来可以增强这些特性。