Ghrelin and Traumatic Brain Injury

描述（由申请人提供）：创伤性脑损伤（TBI）患者经常发生胃肠道功能障碍。超过50%的严重颅脑损伤患者会出现胃肠道功能障碍。不能维持胃肠道功能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功能障碍的相关性表明中枢神经系统和胃肠系统之间存在密切联系。然而，胃肠系统的改变是否参与调节TBI后神经元的损伤和恢复在很大程度上被忽视。在这个建议中，我们将集中在胃肠激素，生长激素释放肽，在脑外伤后脑损伤的发展中的作用。最初报道Ghrelin通过刺激中枢神经系统中的Ghrelin受体来诱导生长激素释放。然而，大量的证据表明，中枢和外周ghrelin受体介导的ghrelin的其他生理功能。最近的研究表明，ghrelin是一种血管活性肽，具有抗炎作用。脑外伤后的一个主要事件是脑微血管自动调节能力的丧失，这导致持续的低灌注和重要代谢物向脑组织的不适当递送。此外，TBI引发了一系列炎症过程，这些炎症过程可以加剧初始损伤。然而，生长激素释放肽在脑外伤后脑损伤的发展中的作用仍然未知。使用由体重下降诱导的TBI大鼠模型，我们已经表明，胃饥饿素基因表达在TBI后显著降低，并且通过脑室内注射饥饿素受体拮抗剂的中枢饥饿素阻断剂加重了TBI后的脑损伤。因此，我们假设生长激素释放肽的下调有助于持续的低灌注和夸张的炎症反应，并随后加重TBI后的初始损伤。我们将首先确定生长素释放肽和生长素释放肽受体表达的动力学曲线与TBI后脑损伤的相关性，然后确定中枢生长素释放肽替代对TBI后脑损伤的影响。解偶联蛋白-2（UCP2）可防止脑创伤后神经元死亡并减少脑功能障碍。Ghrelin已被证明可以增强UCP2在包括大脑在内的各种器官中的表达。因此，我们假设生长激素释放肽通过上调UCP2在TBI后减轻脑损伤。我们将确定脑创伤动物中生长激素释放肽对皮质和海马UCP2表达的影响，并比较脑创伤后野生型和UCP2基因敲除小鼠中生长激素释放肽对脑损伤和神经学结局的影响。总的来说，拟议的研究将提供有关TBI病理生理学的新机制信息，并可能导致脑损伤患者新的治疗干预的发展。 创伤性脑损伤（TBI）是一个主要的医疗保健问题，也是全球范围内的一个重大社会经济挑战。仅在美国，每年约有200万患者受到影响，严重TBI的死亡率仍高达35%-40%。这些统计数字突出表明，迫切需要有效的治疗方式，以改善创伤后发病率和死亡率。这项建议与公共卫生的相关性是最终使用生长激素释放肽治疗头部受伤的病人。

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.