Neuroprotective Role of Fetuin in Cerebral Ischemia

胎球蛋白在脑缺血中的神经保护作用

• 批准号: 6928407
• 负责人: Haichao Wang
• 金额: $ 33万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6928407
• 关键词: alpha globulin; blood brain barrier; cerebral ischemia /hypoxia; cytotoxicity; immune response; immunocytochemistry; immunoregulation; inflammation; laboratory mouse; laboratory rat; microinjections; neuroprotectants

DESCRIPTION (provided by applicant): Despite recent advances in prevention and therapy, stroke remains the leading cause of long-term disability and the third most common cause of death in the United States. A major conceptual advance in understanding the pathophysiology of stroke was the identification of two distinct stages of disease progression: primary tissue damage in the ischemic core, and secondary tissue injury in the surrounding penumbra. The inflammatory response elicited by cerebral ischemia is a promising target for pharmaceutical intervention of stroke, because it progresses over many hours after stroke, and exacerbates tissue injury. As a feedback regulatory mechanism, an endogenous ubiquitous molecule, spermine, accumulates at sites of injury, and inhibits the release of various proinflammatory cytokines. Sperminemediated immune suppression is dependent on the negative acute phase protein, fetuin, which is significantly increased in the brains of animals subjected to experimental cerebral ischemia (middle cerebral artery occlusion, MCAO). Furthermore, peripheral administration of exogenous fetuin immediately after MCAO confers dose-dependent protection against cerebral ischemic injury at 24 hours after MCAO. Several important questions remain unanswered regarding the long-term neuroprotective efficacy of fetuin, and the mechanisms underlying ischemia-elicited elevation of brain fetuin levels, as well as the fetuin-mediated neuroprotection against cerebral ischemic injury. We will first determine the long-term effects of inhibiting (by intracerebral administration of fetuin-specific antibodies or genetic disruption of fetuin expression) or augmenting (by intravenous or intracerebroventricular administration of exogenous fetuin) cerebral fetuin levels on cerebral ischemic injury (Specific Aim 1). To delineate the mechanisms underlying ischemia-induced increase of brain fetuin levels, we will determine whether fetuin in the ischemic brain tissue is produced locally by the central nervous system, or obtained (across the blood-brain barrier) from the peripheral circulation (Specific Aim 2). Lastly, we will delineate the specific mechanisms of fetuin-mediated neuronal protection by determining whether administration of fetuin alters expression of proinflammatory cytokines (such as TNF and HMGB1), or animal physiological parameters such as blood pressure and organ perfusion (Specific Aim 3). Answers to these questions will improve our understanding of the pathophysiology of ischemic neural injury, and identify novel therapeutic agents for the treatment of stroke and related disorders.

描述（由申请人提供）： 尽管最近在预防和治疗方面取得了进展，但中风仍然是美国长期残疾的主要原因和第三大常见死因。在理解卒中病理生理学方面的一个主要概念性进展是确定了疾病进展的两个不同阶段：缺血核心的原发性组织损伤和周围半影区的继发性组织损伤。脑缺血引起的炎症反应是卒中药物干预的一个有前途的靶点，因为它在卒中后数小时内进展，并加剧组织损伤。作为一种反馈调节机制，内源性普遍存在的分子精胺在损伤部位积累，并抑制各种促炎细胞因子的释放。精子介导的免疫抑制依赖于负性急性期蛋白胎球蛋白，胎球蛋白在实验性脑缺血（大脑中动脉闭塞，MCAO）动物的脑中显著增加。此外，MCAO后立即外周给予外源性胎球蛋白可在MCAO后24小时对脑缺血性损伤产生剂量依赖性保护作用。关于胎球蛋白的长期神经保护作用、缺血引起的脑胎球蛋白水平升高的机制以及胎球蛋白介导的脑缺血性损伤神经保护作用的几个重要问题仍未得到解答。我们将首先确定抑制（通过脑内给予胎球蛋白特异性抗体或胎球蛋白表达的遗传破坏）或增加（通过静脉内或脑室内给予外源性胎球蛋白）脑胎球蛋白水平对脑缺血性损伤的长期影响（具体目标1）。为了描述缺血诱导的脑胎球蛋白水平升高的潜在机制，我们将确定缺血脑组织中的胎球蛋白是由中枢神经系统局部产生，还是从外周循环获得（穿过血脑屏障）（具体目的2）。最后，我们将通过确定胎球蛋白给药是否改变促炎细胞因子（如TNF和HMGB1）的表达或动物生理参数（如血压和器官灌注）来描述胎球蛋白介导的神经元保护的具体机制（具体目标3）。这些问题的答案将提高我们对缺血性神经损伤的病理生理学的理解，并确定治疗中风和相关疾病的新的治疗药物。