Neuroprotective Role of Fetuin in Cerebral Ischemia

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，但在美国，中风仍然是导致长期残疾的主要原因和第三大最常见的死亡原因。在理解中风的病理生理学方面，一个主要的概念性进展是确定了疾病进展的两个不同阶段：缺血核心的初级组织损伤和周围半暗带的继发性组织损伤。脑缺血引起的炎症反应是卒中药物干预的一个有前景的靶点，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，内源性的普遍存在的分子精胺在损伤部位积聚，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阴性的急性时相蛋白胎球蛋白，在实验性脑缺血(大脑中动脉闭塞，MCAO)动物的脑中，胎球蛋白显著增加。此外，在MCAO后立即外周注射外源性胎球素对MCAO后24小时的脑缺血损伤具有剂量依赖性的保护作用。关于胎球蛋白的长期神经保护作用、脑缺血引起的胎球蛋白水平升高的机制以及胎球蛋白介导的抗脑缺血损伤的神经保护作用，仍有几个重要的问题尚未回答。我们将首先确定抑制(通过脑内注射胎球蛋白特异性抗体或基因干扰胎儿蛋白表达)或增强(通过静脉或脑室内注射外源性胎儿蛋白)脑内胎儿蛋白水平对脑缺血损伤的长期影响(特定目标1)。为了阐明脑缺血导致胎球蛋白水平升高的机制，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的，还是(跨越血脑屏障)从外周循环获得的(特定目标2)。最后，我们将通过确定给予胎儿蛋白是否改变促炎细胞因子(如肿瘤坏死因子和HMGB1)的表达，或改变动物生理参数如血压和器官灌注量(特定目标3)来描述胎儿蛋白介导的神经元保护的具体机制。对这些问题的回答将提高我们对缺血性神经损伤的病理生理学的理解，并找到治疗中风和相关疾病的新的治疗药物。

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.