Ghrelin and Traumatic Brain Injury

描述（由申请人提供）：胃肠功能障碍是创伤性脑损伤（TBI）患者常见的症状。超过50%的严重头部损伤患者会出现胃肠功能障碍。胃肠功能不能维持是创伤后发病率和死亡率的重要原因。脑损伤的严重程度与胃肠道功能障碍之间的联系表明中枢神经系统和胃肠道系统之间存在着密切的联系。然而，胃肠道系统的改变是否参与脑外伤后神经元损伤和恢复的调节在很大程度上被忽视了。在本提案中，我们将重点关注胃肠激素ghrelin在TBI后脑损伤发展中的作用。Ghrelin最初被报道通过刺激中枢神经系统的Ghrelin受体来诱导生长激素的释放。然而，大量证据表明，胃饥饿素的其他生理功能是由中枢和外周胃饥饿素受体介导的。近年来的研究表明，胃饥饿素是一种血管活性肽，具有抗炎特性。脑外伤后的一个主要事件是脑微血管自身调节能力的丧失，导致持续的灌注不足和重要代谢物向脑组织的不适当递送。此外，TBI启动了一系列炎症过程，可以加重初始损伤。然而，胃饥饿素在脑外伤后脑损伤发展中的作用尚不清楚。通过体重下降诱导的大鼠脑外伤模型，我们发现胃饥饿素基因表达在脑外伤后显著降低，脑室内注射胃饥饿素受体拮抗剂阻断中枢胃饥饿素会加重脑外伤后的脑损伤。因此，我们假设ghrelin的下调有助于持续的灌注不足和夸大的炎症反应，并随后加剧TBI后的初始损伤。我们将首先确定胃饥饿素和胃饥饿素受体表达的动力学特征与脑外伤后脑损伤的相关性，然后确定中枢胃饥饿素替代对脑外伤后脑损伤的影响。解偶联蛋白-2 （UCP2）可防止脑外伤后神经元死亡并减少脑功能障碍。Ghrelin已被证明在包括大脑在内的各种器官中增强UCP2的表达。因此，我们假设胃饥饿素通过上调脑外伤后的UCP2来减轻脑损伤。我们将确定ghrelin对TBI动物皮质和海马UCP2表达的影响，并比较ghrelin对脑外伤后野生型和UCP2敲除小鼠脑损伤和神经预后的影响。总的来说，这些研究将为TBI的病理生理学提供新的机制信息，并可能导致对脑损伤患者的新治疗干预的发展。

DESCRIPTION (provided by applicant): Gastrointestinal dysfunction occurs frequently in patients with traumatic brain injury (TBI). More than 50% of patients with severe head injuries develop gastrointestinal dysfunction. Failure to maintain gastrointestinal function is a significant cause of post-trauma morbidity and mortality. The association of severity of brain injury with gastrointestinal dysfunction suggests a strong link between the central nervous system and the gastrointestinal system. However, whether alterations in the gastrointestinal system are involved in modulating neuronal damage and recovery after TBI is largely neglected. In this proposal, we will focus on the role of a gastrointestinal hormone, ghrelin, in the development of brain injury after TBI. Ghrelin was originally reported to induce growth hormone release through stimulation of ghrelin receptors in the central nervous system. However, a large body of evidence has indicated other physiological functions of ghrelin mediated by the central and peripheral ghrelin receptors. Recent studies have demonstrated that ghrelin is a vasoactive peptide and possesses anti- inflammatory properties. A major event following brain trauma is the loss of autoregulatory capacity of brain microvessels which results in sustained hypoperfusion and improper delivery of vital metabolites to the brain tissue. Moreover, TBI initiates a cascade of inflammatory processes that can serve to exacerbate the initial injury. However, the role of ghrelin in the development of brain injury after TBI remains unknown. Using a rat model of TBI induced by weight drop, we have shown that ghrelin gene expression in the stomach is significantly reduced after TBI and central ghrelin blockade through intracerebroventricular injection of ghrelin receptor antagonists exacerbates brain injury after TBI. We therefore hypothesize that downregulation of ghrelin contributes to the sustained hypoperfusion and exaggerated inflammatory responses, and subsequently exacerbates the initial injury after TBI. We will first determine the correlation of the kinetic profiles of ghrelin and ghrelin receptor expression with brain injury after TBI and then determine the effect of central ghrelin replacement on brain injury following TBI. Uncoupling protein-2 (UCP2) prevents neuronal death and diminishes brain dysfunction after brain trauma. Ghrelin has been shown to enhance UCP2 expression in various organs including the brain. Thus, we hypothesize that ghrelin attenuates brain injury via upregulation of UCP2 after TBI. We will determine the effects of ghrelin on cortex and hippocampus UCP2 expression in TBI animals and compare ghrelin's effects on brain injury and neurological outcome in wild-type and UCP2 knockout mice following brain trauma. Collectively, the proposed studies will provide novel mechanistic information about the pathophysiology of TBI, and may lead to the development of a new therapeutic intervention for patients with brain injury. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) represents a major health care problem and a significant socioeconomic challenge worldwide. In the United States alone, approximately 2 million patients are affected each year, and the mortality of severe TBI remains as high as 35%-40%. These statistics underline the urgent need for efficient treatment modalities to improve posttraumatic morbidity and mortality. The relevance of this proposal to public health is to eventually use ghrelin in the treatment of patients with head injury.