Corticotropin Releasing Factor: Impact on Inflammation

描述（由申请人提供）：神经内分泌和免疫系统双向交流，这部分是通过神经肽激素和细胞因子介导的。在这种交流中，一个最有趣但又最不为人所知的方面是白细胞可以合成神经肽激素。虽然生产是可重复的和良好的记录，白细胞衍生的神经肽的基本作用尚不清楚。白细胞产生神经肽的重要性一直难以评估，部分原因是在体内它们是在神经内分泌系统的背景下产生的，其神经肽的贡献要大得多。促肾上腺皮质激素释放因子（CRF）是这些白细胞衍生的神经肽之一，是一种特别有趣的调节剂，对神经内分泌和免疫反应有许多影响，可能是这些系统之间的关键调节剂。研究表明，CRF可能抑制或增强特定的免疫反应。我们的假设是，白细胞产生的CRF调节炎症，至少在局部部位通过特定受体。这是一项探索性/发展性建议，旨在开发一种白细胞是CRF唯一来源的小鼠模型。这可以用来确定白细胞衍生的CRF在体内的作用。在未来的研究中，它也可以作为研究其他白细胞衍生神经肽的模型。具体来说，我们的目标是：1)在炎症和抗体产生的体内模型中识别和定位CRF的产生和CRF受体亚型。2)培养仅白细胞产生CRF的嵌合小鼠，并测试白细胞产生CRF调节炎症过程的能力。该项目应显示CRF在炎症反应中的重要性。有实验证据表明，CRF与人类的几种炎症性疾病有关，包括关节炎、哮喘和炎症性肠病，而且它可能在多发性硬化症中发挥作用。新的CRF受体拮抗剂正在开发中，一旦了解，可能有助于治疗这些疾病中炎症部位的浸润性白细胞。这个项目的目标是确定神经肽，促肾上腺皮质激素释放因子在炎症中的重要性。炎症性疾病是疾病和死亡的主要原因，了解炎症的调节应该允许开发针对这些疾病的靶向和强大的新疗法。

DESCRIPTION (provided by applicant): The neuroendocrine and immune systems communicate bi-directionally and this is mediated in part through neuropeptide hormones and cytokines. One of the most interesting yet least understood aspects of this communication is that leukocytes can synthesize neuropeptide hormones. While the production is reproducible and well documented, the fundamental role of leukocyte-derived neuropeptides is not known. The significance of leukocyte production of neuropeptides has been difficult to assess, in part because in vivo they are produced in the context of the neuroendocrine system and its much larger contribution of neuropeptide. One of these leukocyte-derived neuropeptides, corticotropin releasing factor (CRF) is a particularly interesting regulator that has many effects on neuroendocrine and immune responses and may be a key regulator between these systems. Studies have shown that CRF may suppress or enhance selected immune responses. Our hypothesis is that leukocyte production of CRF modulates inflammation, at least at the local site through specific receptors. This is an exploratory/developmental proposal to develop a mouse model in which the leukocytes are the sole source of CRF. This could then be used to determine what the role of leukocyte-derived CRF may be in vivo. It could also serve as a model to study other leukocyte-derived neuropeptides in future studies. Specifically we aim to: 1) To identify and localize CRF production and CRF receptor subtypes in an in vivo model of inflammation and antibody production. 2) To develop a chimeric mouse in which only the leukocytes produce CRF and to test the ability of leukocyte CRF production to modulate an inflammatory process. This project should show the importance of CRF in an inflammatory response. There is experimental evidence to suggest that CRF is involved in several inflammatory diseases of humans including arthritis, asthma, and inflammatory bowel diseases plus it could possibly play a role in multiple sclerosis. New CRF receptor antagonists are being developed and once understood might be useful in therapies that could be directed at the infiltrating leukocytes at the sites of inflammation in these diseases. This project's goal is to determine the importance of a neuropeptide, corticotropin releasing factor in inflammation. Inflammatory diseases are a major cause of illness and death and understanding the regulation of inflammation should allow the development of targeted and powerful new treatments for these diseases.