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，部分通过神经肽激素和细胞因子介导。白细胞可以合成神经肽激素，这是白细胞之间最有趣但最不为人所知的一个方面。虽然生产是可重复的和有据可查的，白细胞衍生的神经肽的基本作用是未知的。白细胞产生神经肽的意义一直难以评估，部分原因是它们在体内是在神经内分泌系统的背景下产生的，神经肽的贡献要大得多。促肾上腺皮质激素释放因子（CRF）是一种特别有趣的调节因子，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因子。研究表明，CRF可抑制或增强选定的免疫应答。我们的假设是CRF的白细胞产生调节炎症，至少在局部通过特异性受体。这是一项开发小鼠模型的探索性/开发性建议，其中白细胞是CRF的唯一来源。这可以用来确定白细胞衍生的CRF在体内的作用。它也可以作为一个模型，在未来的研究中研究其他白细胞衍生的神经肽。具体而言，我们的目标是：1）在炎症和抗体产生的体内模型中鉴定和定位CRF产生和CRF受体亚型。2)建立一种仅白细胞产生CRF的嵌合小鼠，并检测白细胞产生CRF调节炎症过程的能力。这个项目应该显示CRF在炎症反应中的重要性。有实验证据表明，CRF参与人类的几种炎症性疾病，包括关节炎，哮喘和炎症性肠病，并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，一旦了解可能是有用的治疗，可以直接在这些疾病的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治疗方法。

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.