Hematopoietic Growth Factors and Chronic Stroke

造血生长因子与慢性中风

• 批准号: 8247103
• 负责人: LI-RU ZHAO
• 金额: $ 16.21万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8247103
• 关键词: Abbreviations; Address; Adult; Agaricales; Analysis of Variance; Animals; Blood; Blood - brain barrier anatomy; Blood Cells; Blood Vessels; Bone Marrow; Bone Marrow Cells; Bone Marrow Stem Cell; Bone Marrow Transplantation; Brain; Brain Injuries; Calgranulin A; Cell Culture Techniques; Cells; Cerebrum; Chemicals; Chemotactic Factors; Common carotid artery; Complement; Cyan Fluorescent Protein; Data; Dendritic Spines; Development; Elderly; Elements; Enzyme-Linked Immunosorbent Assay; Evaluation; Gene Expression; Gene Silencing; Granulocyte Colony-Stimulating Factor; Green Fluorescent Proteins; Hematopoietic Cell Growth Factors; Homing; Hydroxyl Radical; Image; In Vitro; Inbred SHR Rats; Incidence; Infarction; Ischemic Stroke; Isoxazoles; Knowledge; Laboratories; Lead; Life; Link; MEKs; Mediating; Migration Assay; Mission; Modeling; Mononuclear; Mus; N-Methylaspartate; Natural regeneration; Neurites; Neurodegenerative Disorders; Neurologic; Neurons; Nuclear; PIK3CG gene; Pathway interactions; Pattern; Penetration; Permeability; Pharmacologic Substance; Phase; Phosphate Buffer; Photons; Play; Population; Population Density; Production; Propionic Acids; Proteins; Proto-Oncogene Protein c-kit; Public Health; Publications; RNA Interference; Rattus; Recovery of Function; Regulation; Research; Reverse Transcriptase Polymerase Chain Reaction; Reverse Transcription; Role; S100A8 gene; Saline; Signal Pathway; Signal Transduction; Small Interfering RNA; Stem Cell Factor; Stroke; Subcutaneous Injections; Synapses; Testing; Therapeutic; Time; Transgenic Organisms; United States; United States National Institutes of Health; Up-Regulation; Vertebral column; Western Blotting; aged; base; brain repair; cell motility; cell type; chronic stroke; defined contribution; design; disability; functional improvement; functional outcomes; functional restoration; improved; in vivo; innovation; insight; middle cerebral artery; nervous system disorder; neuronal circuitry; novel therapeutics; public health relevance; repaired; research study; treatment strategy

DESCRIPTION (provided by applicant): Stroke, a neurological disorder with a high incidence in the elderly, is a leading cause of long-term disability in adults worldwide. Stroke is also an enormous public health problem and a serious public financial burden in the United States. Chronic stroke is identified as the period beyond 3-6 months after stroke onset. Currently, no pharmaceutical treatment is available for chronic stroke victims. Stem cell factor (SCF) and granulocyte- colony stimulating factor (G-CSF) are hematopoietic growth factors (HGFs) that regulate blood cell production and mobilize bone marrow stem cells (BMSCs) into the blood. Our recent publications have shown that the receptors for SCF and G-CSF are expressed by neurons, that both SCF and G-CSF can pass through the blood-brain barrier, and, more importantly, that SCF in combination with G-CSF (SCFCSF) shows therapeutic benefits for chronic stroke in a rat model of stroke. However, it remains entirely unknown how SCFCSF repairs a permanently damaged brain during chronic stroke. The objective of this project is to address this unanswered question. Supported by considerable preliminary data, the central hypothesis is that neuronal network remodeling contributes to SCFCSF-induced functional recovery in chronic stroke and that the neuronal network remodeling is accomplished by the direct effects of SCFCSF on neurons and the indirect effects via BMSCs. Using neuronal and BMSC cultures together with stroke models in aged spontaneously hypertensive rats and in aged wild type or transgenic C57 BL mice expressing yellow or cyan fluorescent proteins only in neurons (Thy-1-YFP, Thy-1-CFP), and bone marrow transplantation to track BMSCs, this hypothesis will be tested by pursuing two specific aims. Aim #1 is to determine whether SCF CSF-induced functional benefits in chronic stroke are dependent upon MEK/ERK and PI3k/Akt pathway- mediated neuronal network remodeling. Western blots, cell signaling blockade, RNA interference, 2-photon live imaging and neurological deficit examinations will be used. Aim #2 is to identify the role of the S100A8/A9 chemical gradient established by SCFCSF in homing BMSCs to the brain and to determine the contribution of the BMSCs to SCFCSF-induced functional recovery from chronic stroke. BMSC migration assays, S100A8/A9 gene silencing by RNA interference, and sensorimotor functional evaluation will be utilized. The proposed research is significant because it will advance and extend understanding of how HGFs repair the brain after permanent damage by stroke. Additionally, it will significantly contribute to the development of a unique therapeutic strategy for treatment of chronic stroke. This contribution is in keeping with the NIH mission to reduce national and personal burdens caused by illness and disability. PUBLIC HEALTH RELEVANCE: The proposed study focuses on a highly important, but under-investigated topic: a new therapeutic strategy to treat chronic stroke in the aged population. This research is directly relevant to public health. The findings can provide fresh insights into the contribution of hematopoietic growth factors in brain repair. Additionally, this knowledge may also lead to the development of new treatments for other neurological disorders and neurodegenerative diseases.

描述（由申请人提供）：中风，一种在老年人中发病率高的神经系统疾病，是全球成人长期残疾的主要原因。中风也是美国巨大的公共卫生问题，也是美国的严重公共财务负担。慢性中风被确定为中风发作后3-6个月以上的时期。目前，慢性中风受害者没有药物治疗。干细胞因子（SCF）和粒细胞刺激因子（G-CSF）是造血生长因子（HGFS），可调节血细胞的产生并动员骨髓干细胞（BMSC）。我们最近的出版物表明，SCF和G-CSF的受体由神经元表达，SCF和G-CSF均可通过血脑屏障，更重要的是，SCF与G-CSF（SCFCSF）结合使用，在Stroke的大鼠大鼠模型中，SCF与G-CSF（SCFCSF）结合使用。但是，在慢性中风期间，SCFCSF如何维修长期损害的大脑仍然完全未知。该项目的目的是解决这个未解决的问题。在大量初步数据的支持下，中心假设是神经元网络重塑有助于SCFCSF诱导的慢性中风的功能恢复，并且神经元网络重塑是通过SCFCSF对神经元的直接影响来实现的，而神经元对BMSCS的间接影响。使用神经元和BMSC培养物，以及在自发性高血压大鼠以及型野生型或转基因的C57 BL小鼠中，仅在神经元（THY-1-YFP，THY-1-CFP）中表达黄色或氰基荧光蛋白的年龄型野生型或转基因C57 BL小鼠，以及通过Track bmscs进行bmscses的骨骼，可通过测试效果。 AIM＃1是确定SCF CSF诱导的慢性中风功能益处是否取决于MEK/ERK和PI3K/AKT途径 - 介导的神经元网络重塑。将使用蛋白质印迹，细胞信号阻塞，RNA干扰，2光片实时成像和神经赤字检查。 AIM＃2是确定SCFCSF在将BMSC归为大脑中建立的S100A8/A9化学梯度的作用，并确定BMSCS对SCFCSF诱导的功能恢复的贡献。 BMSC迁移测定，S100A8/A9基因通过RNA干扰沉默，将使用感觉运动功能评估。拟议的研究之所以重要，是因为它将在永久性损害后，可以提高并扩展对HGF如何修复大脑的理解。此外，它将极大地有助于制定慢性中风治疗的独特治疗策略。这项贡献符合NIH的使命，以减轻由疾病和残疾造成的国家和个人负担。 公共卫生相关性：拟议的研究重点是一个非常重要但不足的主题：一种治疗老年人群慢性中风的新治疗策略。这项研究与公共卫生直接相关。这些发现可以为造血生长因子在脑修复中的贡献提供新的见解。此外，这种知识还可能导致开发其他神经系统疾病和神经退行性疾病的新疗法。