Corticotropin Releasing Factor: Impact on Inflammation

描述(申请人提供)：神经内分泌和免疫系统双向交流，这在一定程度上是通过神经肽激素和细胞因子来调节的。这种交流最有趣但最鲜为人知的方面之一是白细胞可以合成神经肽激素。虽然这种产物是可重复性的，并且有很好的文献记载，但白细胞衍生神经肽的基本作用尚不清楚。神经肽的白细胞产生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及其更大的神经肽贡献的背景下产生的。促肾上腺皮质激素释放因子(CRF)是这些白细胞来源的神经肽之一，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可以抑制或增强选定的免疫反应。我们的假设是，CRF的白细胞产生至少通过特定的受体在局部部位调节炎症。这是一项探索性/发展性的建议，旨在建立一种以白细胞为唯一来源的慢性肾功能衰竭小鼠模型。这可以用来确定白细胞来源的CRF在体内可能起到什么作用。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。具体地说，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)建立只有白细胞产生CRF的嵌合小鼠，并检测白细胞产生CRF调节炎症过程的能力。这个项目应该表明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，此外它还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，可能有助于针对这些疾病炎症部位的浸润性白细胞的治疗。该项目的目标是确定一种神经肽--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有助于开发针对这些疾病的有针对性和强大的新疗法。

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.