Functional recovery from acute brain injury via human neural stem cell transplantation

通过人类神经干细胞移植从急性脑损伤中恢复功能

基本信息

批准号：
9315177
负责人：
JASON P WEICK
金额：
$ 26.54万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9315177
关键词：
Acute Acute Brain Injuries Address Adult Adverse effects Aging American Anatomy Animal Model Animals Baby Booms Behavior Behavioral Brain Cause of Death Cell Transplantation Cell Transplants Cells Cerebral Ischemia Chronic Clinical Clinical Trials Data Dependence Disabled Persons Epidemic Future Generations Goals Health Heart Diseases Human In Vitro Incidence Individual Inflammation Injury Intervention Investigation Ischemia Ischemic Brain Injury Ischemic Stroke Mediating Modeling Motor Neuronal Plasticity Neurons New Mexico Optics Outcome Output Pathway interactions Patients Peripheral Phase I Clinical Trials Physiological Plant Roots Prevention Process Recovery Recovery of Function Recruitment Activity Replacement Therapy Reporting Safety Sensorimotor functions Sensory Societies Stem cells Stroke Survivors Synapses Testing Therapeutic Intervention Time Tissues Transplantation Treatment Efficacy United States Universities angiogenesis base behavioral outcome brain cell brain parenchyma brain tissue cell type cost disability effective therapy experimental study human embryonic stem cell human pluripotent stem cell human stem cells improved in vivo insight ischemic lesion mouse model nerve stem cell nerve supply neurotransmitter release optogenetics paracrine pre-clinical preclinical study progenitor relating to nervous system repaired sensory system simulation stroke recovery stroke survivor stroke therapy vesicular release

Acute Acute Brain Injuries Address Adult Adverse effects Aging American Anatomy Animal Model Animals Baby Booms Behavior Behavioral Brain Cause of Death Cell Transplantation Cell Transplants Cells Cerebral Ischemia Chronic Clinical Clinical Trials Data Dependence Disabled Persons Epidemic Future Generations Goals Health Heart Diseases Human In Vitro Incidence Individual Inflammation Injury Intervention Investigation Ischemia Ischemic Brain Injury Ischemic Stroke Mediating Modeling Motor Neuronal Plasticity Neurons New Mexico Optics Outcome Output Pathway interactions Patients Peripheral Phase I Clinical Trials Physiological Plant Roots Prevention Process Recovery Recovery of Function Recruitment Activity Replacement Therapy Reporting Safety Sensorimotor functions Sensory Societies Stem cells Stroke Survivors Synapses Testing Therapeutic Intervention Time Tissues Transplantation Treatment Efficacy United States Universities angiogenesis base behavioral outcome brain cell brain parenchyma brain tissue cell type cost disability effective therapy experimental study human embryonic stem cell human pluripotent stem cell human stem cells improved in vivo insight ischemic lesion mouse model nerve stem cell nerve supply neurotransmitter release optogenetics paracrine pre-clinical preclinical study progenitor relating to nervous system repaired sensory system simulation stroke recovery stroke survivor stroke therapy vesicular release

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项目摘要

SUMMARY Stroke represents a major health issue not only as a cause of death but because most people survive their first stroke, leaving victims permanently disabled. With an aging baby boom generation in the United States, incidence of stroke and costs to society propose to reach epidemic proportions within the next two decades. While prevention efforts have significantly reduced lethality, few effective treatment options exist to provide patients with a means of recovery, and none exist to address the root cause of the problem, loss of brain tissue. Recently however, successful outcomes from cell replacement therapies in pre-clinical studies have led to a number of clinical trials which have demonstrated safety and efficacy for a variety of cell types. Interestingly, many of the mechanisms attributed to transplanted mediated recovery converge on the activity- regulated release of paracrine factors from transplant to host. In the current study, we propose first to validate that transplanted human pluripotent stem cell-derived neurons (hPSNs) improve behavioral recovery in a mouse model of focal ischemia that is amenable to mechanistic and manipulation studies (Specific Aim 1). We will then use this model to test whether optogenetic stimulation of hPSNs can augment behavioral recovery from stroke (Specific Aim 2). Lastly, multiple lines of evidence suggest that functional integration of transplanted cells with host tissue is critical for long-term benefits of cell replacement. In support of this, we have recently demonstrated in uninjured animals that human embryonic stem cell-derived neurons (hPSNs) can functionally integrate with host circuitry after transplantation, and can cause changes to overall excitability in vitro. In the Specific Aim 3 we will test whether and how transplanted hPSNs are functionally integrating with host circuits in vivo to understand how we might augment future intervention strategies. The impact of answering these questions proposes to improve efficacy of cell-based therapeutic interventions.

概括中风不仅是死亡原因，而且是大多数人幸存下来的一个主要健康问题中风，使受害者永久残疾。在美国，婴儿繁荣的一生，中风的发病率和对社会成本的发病率建议在未来二十年内达到流行比例。尽管预防努力大大降低了致死率，但几乎没有有效的治疗选择来提供具有康复手段的患者，没有任何解决问题根本原因的患者组织。然而，最近，临床前研究中细胞替代疗法的成功结果已导致许多临床试验证明了各种细胞类型的安全性和功效。有趣的是，归因于移植的介导的恢复的许多机制在活动上融合从移植到宿主的旁分泌因子的调节释放。在当前的研究中，我们首先提议验证移植的人多能干细胞衍生的神经元（HPSN）改善了行为恢复局灶性缺血的小鼠模型可与机械和操纵研究相提并论（特定目标1）。我们然后将使用此模型测试HPSN的光遗传学刺激是否可以增加行为恢复来自中风（特定目标2）。最后，多种证据表明功能整合带有宿主组织的移植细胞对于长期替代细胞的益处至关重要。为此，我们最近在未受伤的动物中证明了人类干细胞衍生的神经元（HPSN）移植后可以在功能上与主机电路集成，并可能导致整体兴奋性的变化体外。在特定目的3中，我们将测试移植的HPSN是否以及如何在功能上集成主机在体内电路，以了解我们如何增强未来的干预策略。的影响回答这些问题提出提高基于细胞的治疗干预措施的功效。