Ghrelin and Traumatic Brain Injury

描述(申请人提供)：创伤性脑损伤(TBI)患者经常出现胃肠功能障碍。超过50%的重型颅脑损伤患者会出现胃肠功能障碍。未能维持胃肠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之间的关联表明，中枢神经系统和胃肠系统之间存在着强烈的联系。然而，胃肠道系统的改变是否参与了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。在这项提案中，我们将重点讨论胃肠激素Ghrelin在脑外伤后脑损伤发展过程中的作用。Ghrelin最初被报道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，大量证据表明，Ghrelin的其他生理功能是由中枢和外周Ghrelin受体介导的。最近的研究表明，Ghrelin是一种血管活性多肽，具有抗炎作用。脑创伤后的一个主要事件是脑微血管自身调节能力的丧失，导致持续的低灌流和重要代谢产物向脑组织的不当输送。此外，创伤性脑损伤会引发一连串的炎症过程，从而加重最初的损伤。然而，Ghrelin在脑外伤后脑损伤发生发展中的作用仍不清楚。在减重致大鼠颅脑损伤模型上，我们发现颅脑损伤后胃内Ghrelin基因的表达显著降低，通过侧脑室注射Ghrelin受体拮抗剂阻断中枢Ghrelin可加重脑损伤。因此，我们假设Ghrelin的下调参与了持续的低灌流和过度的炎症反应，并随后加重了创伤性脑损伤后的最初损伤。我们将确定Ghrelin和Ghrelin受体的动态表达与脑损伤后的相关性。解偶联蛋白-2(UCP2)可防止脑创伤后神经元死亡，减轻脑功能障碍。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Ghrelin通过上调UCP2的表达来减轻脑损伤。我们将确定Ghrelin对脑创伤动物脑内UCP2表达的影响，然后确定UCP2在脑创伤后Ghrelin保护作用中的作用。总之，拟议的研究将提供有关脑外伤病理生理学的新的机制信息，并可能导致开发一种新的脑损伤患者的治疗干预措施。 公共卫生相关性：创伤性脑损伤(TBI)是世界范围内的一个重大卫生保健问题和重大的社会经济挑战。仅在美国，每年就有大约200万名患者受到影响，重型颅脑损伤的死亡率仍高达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将Ghrelin用于头部损伤患者的治疗。

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 determine the correlation of the kinetic profiles of ghrelin and ghrelin receptor expression with brain injury after 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 brain UCP2 expression in TBI animals and then determine the contribution of UCP2 on ghrelin's protective effects after TBI. 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.