Protective monocytes in cerebral ischemic tolerance

脑缺血耐受中的保护性单核细胞

• 批准号: 8544515
• 负责人: Josef Anrather
• 金额: $ 35.67万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544515
• 关键词: Acute; Adoptive Transfer; Animals; Automobile Driving; Biological Preservation; Blood; Blood - brain barrier anatomy; Blood flow; Brain; Brain Death; Brain Injuries; Cell Therapy; Cells; Cerebral Ischemia; Cerebrum; Clinical Trials; Cytoprotection; Disease; Engraftment; Flow Cytometry; Genes; Glucose; Goals; Immune; Immune response; Immune system; Immunosuppression; Inflammatory; Intrinsic factor; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Knockout Mice; Ligands; Lipopolysaccharides; Molecular; Mus; Neurological outcome; Neurons; Organ; Oxygen; Pathway interactions; Play; Population; Recruitment Activity; Research; Role; Stimulus; Stress; Stroke; Testing; Therapeutic; Time; base; cell type; cellular targeting; clinically relevant; deprivation; in vivo; insight; macrophage; meetings; monocyte; mouse model; nervous system disorder; neuroprotection; novel; novel therapeutic intervention; preconditioning; programs; protective effect; success; toll-like receptor 4; trafficking

DESCRIPTION (provided by applicant): Stroke is a highly prevalent and devastating disease with limited therapeutic options. Most efforts to develop treatments for stroke have thus far met with limited success in large clinical trials. The brain has an enormous capacity for self-preservation, and elucidating how the brain protects itself may provide novel insights into stroke treatment. Ischemic tolerance (IT), a phenomenon in which application of sub-lethal stress [preconditioning (PC) stimulus; PC] induces a state of tolerance to a subsequent ischemic insult, represents an example of endogenous neuroprotection. IT can be induced in brain by systemic administration of the Toll-like receptor-4 ligand lipopolysaccharide (LPS). Different populations of immune cell could potentially play a role in PC induced by LPS. In particular, monocytes, which are the main target of LPS, can exert a powerful protective effect either directly or by modulating the immune system. However, it remains to be established whether monocytes or other immune cells play a role in the IT induced by LPS. The identification of the cell type(s) responsible for LPS induced IT would be important as it would offer the prospect of novel therapies for ischemic stroke based on these protective immune cells. This application will test the hypothesis that LPS PC induces brain engraftment of protective monocytic cells that ameliorate ischemic brain injury either directly or by modulating the immune response to cerebral ischemia. To this end, we will determine (a) the origin of neuroprotective monocytic subtypes, (b) the molecular factors driving their entry into the brain, and (c) the mechanisms by which they confer neuroprotection. Furthermore, we will determine whether these cells can be adoptively transferred to protect animals from experimental stroke with a clinically relevant therapeutic window. These goals will be achieved using a mouse model of transient focal cerebral ischemia with assessment of histological and neurological outcome. The effect of LPS PC on immune cell populations will be assessed by flow cytometry.

描述（由申请人提供）：中风是一种高度普遍且毁灭性的疾病，治疗选择有限。到目前为止，在大型临床试验中，开发中风治疗的大多数努力已经取得了有限的成功。大脑具有巨大的自我保护能力，并阐明大脑如何保护自己可以为中风治疗提供新的见解。缺血性耐受性（IT），这种现象在这种现象中使用亚致死应激[预处理（PC）刺激； PC]诱导对随后的缺血性侮辱的耐受性，代表了内源性神经保护的一个例子。它可以通过全身性地给予Toll样受体-4配体脂多糖（LPS）在大脑中诱导它。不同的免疫细胞种群可能在LPS诱导的PC中起作用。特别是，单核细胞是LP的主要目标，可以直接或通过调节免疫系统发挥强大的保护作用。但是，无论是单核细胞还是其他免疫细胞在LPS诱导的IT中起作用，尚待确定。负责LPS引起的LPS的细胞类型的鉴定将很重要，因为它将基于这些保护性免疫细胞提供新型缺血性疗法的前景。该应用将检验以下假设：LPS PC诱导脑植入保护性单核细胞的脑植入，可直接或通过调节对脑缺血的免疫反应来改善缺血性脑损伤。为此，我们将确定（a）神经保护单核细胞亚型的起源，（b）推动其进入大脑的分子因子，以及（c）它们赋予神经保护作用的机制。此外，我们将确定是否可以通过临床相关的治疗窗口来保护这些细胞以保护动物免受实验性中风。这些目标将使用瞬时局灶性脑缺血的小鼠模型来评估组织学和神经系统结果。 LPS PC对免疫细胞种群的影响将通过流式细胞仪评估。