PYRIN proteins as regulators of innate immune pathways

描述(由申请人提供)：我们正在寻求资金，以回应NOT-OD-09-058“NIH美国复苏法案竞争性修订申请资金”，以使我们能够扩大我们批准的父母奖项的具体目标3。我们的父母奖的所有三个具体目标都是基于分子、细胞和生化研究，以阐明调节巨噬细胞中炎性小体组装和活动的三个新步骤。通过这次修订，我们建议在我们批准的目标3的基础上增加一个新的子目标，将我们的体外研究转化为体内动物模型。基于我们在特定目标3方面的进展，我们建议建立巨噬细胞特异性条件性敲除小鼠，以研究体外敲除巨噬细胞中的炎症体活性，以及体内炎症体依赖性疾病模型中的炎症体活性。我们要求提供资金，以支付这个小鼠模型的生成和动物工作的技术支持。此次修订将扩大我们批准的父母奖的范围，并使我们的实验室能够建立老鼠疾病模型。此次修订的资金将支持2009年《美国复苏与再投资法案》的目标，即创造“新的研究性就业机会”和“支持美国小企业和美国经济”。 公共卫生相关性：IL-12和IL-18的过度产生直接导致越来越多具有破坏性发病机制的炎症性疾病的症状，包括一些工业化国家最常见的疾病，如关节炎、哮喘、炎症性肠病、溃疡性结肠炎、动脉粥样硬化、牙周炎、2型糖尿病、肺纤维化、多发性硬化症、阿尔茨海默病、中风或癌症。目前还没有有效的治疗方法，导致患者的终生症状，并对我们的社会和医疗系统造成巨大的经济和财政影响。因此，这项关于调节IL-12和IL-18产生的新机制的研究有望为开发新的和改进的治疗方案提供基础，从而为预防炎症性疾病患者IL-12和IL-18的失控释放提供基础，从而对人类健康产生积极的影响。

DESCRIPTION (provided by applicant): We are seeking funds in response to NOT-OD-09-058 "NIH American Recovery Act Funds for Competitive Revision Applications" to allow us to expand our specific aim 3 of our approved parent award. All three specific aims of our parent award are based on molecular, cellular, and biochemical studies to elucidate three novel steps in the regulation of inflammasome assembly and activity in macrophages. With this revision, we are proposing to include a novel sub aim to our approved aim 3 to translate our in vitro studies into in vivo animal models. Based on our progress with specific aim 3, we propose to generate a macrophage-specific conditional knock out mouse to study inflammasome activity in knock-out macrophages in vitro, and in inflammasome- dependent disease models in vivo. We request funds to cover the generation of this mouse model and that of technical support for the animal work. This revision will increase the scope of our approved parent award and enable our laboratory to establish mouse disease models. Funding of this revision will support the objectives of the American Recovery and Reinvestment Act of 2009 to create "new research employment opportunities" and "to bolster small US businesses and the US economy". PUBLIC HEALTH RELEVANCE: Excessive production of IL-12 and IL-18 are directly responsible for the symptoms of an increasing number of inflammatory diseases with destructive pathogenesis, including some of the most common diseases of industrialized nations, such as arthritis, asthma, inflammatory bowel disease, ulcerative colitis, atherosclerosis, periodontitis, type 2 Diabetes, lung fibrosis, multiple sclerosis, Alzheimer's disease, stroke, or cancer. Currently there are no effective treatments available, causing patient's life-long symptoms and a huge economical and financial impact on our social and medical systems. Therefore, this study on novel mechanisms that regulate production of IL-12 and IL-18 is expected to positively affect human health by providing the basis for the development of novel and improved treatment options for preventing uncontrolled release of IL-12 and IL-18 in patients suffering from inflammatory diseases.