The Role of Stat5 in Mast Cell Activation and Inflammatory Disease

描述(申请人提供)：肥大细胞是无处不在的炎症介质，多年来一直在研究它们在哮喘、过敏和过敏反应中的作用。然而，近年来出现了新的数据，将肥大细胞与其他各种炎症性疾病联系起来，如动脉粥样硬化性心脏病、自身免疫、宿主对细菌感染的抵抗力和肿瘤血管生成。因此，研究肥大细胞的激活和功能具有广泛的意义，包括开发新的炎症性疾病治疗策略。我们的建议是研究转录因子Stat5在肥大细胞激活和功能中的作用，以及确定Stat5在炎症性疾病中的重要性。我们从小鼠骨髓来源的肥大细胞(BMMCs)收集的初步数据表明，Stat5是肥大细胞功能、存活和增殖的关键调节因子。当研究Stat5对FcepsilonRI信号的主要贡献时，这些影响是最深刻的。免疫球蛋白E交联后，Stat5缺陷的小鼠骨髓单个核细胞脱颗粒明显减少，炎性细胞因子的分泌几乎完全丧失。我们的数据表明，Stat5是肥大细胞相关疾病的潜在重要治疗靶点，这值得研究控制Stat5激活的机制及其在体内的后果。我们的建议分为这两个问题。我们的目标1是确定IgE介导的信号如何激活小鼠和人类肥大细胞中的Stat5，以及Stat5在肥大细胞功能中的作用。通过对Stat5信号通路的了解，我们可以揭示新的治疗策略如何干预这一过程。目的2确定STAT5在体内肥大细胞反应中的重要性。我们将确定Stat5激活在被动全身过敏(PSA)和呼吸道高反应性(AHR)小鼠模型中是否起关键作用。通过这样做，我们可以展示Stat5如何在体内影响炎症反应，这可能表明它作为治疗靶点的可行性。公共卫生相关性：肥大细胞与许多炎症性疾病有关。通过研究肥大细胞的功能，我们可以进一步了解肥大细胞如何影响疾病，并能够发现新的治疗靶点。

DESCRIPTION (provided by applicant): Mast cells are ubiquitous mediators of inflammation and have been studied for a number of years for their role in asthma, allergies, and anaphylaxis. However, in recent years, new data have emerged associating mast cells with a variety of other inflammatory disorders such as atherosclerotic heart disease, autoimmunity, host resistance to bacterial infection, and tumor angiogenesis. Hence, studying mast cell activation and function can have widespread implications including the development of new therapeutic strategies for inflammatory disease. Our proposal is to study the role of the transcription factor Stat5 in mast cell activation and function as well as to determine the importance of Stat5 in inflammatory disease. Our preliminary data collected from mouse bone marrow derived mast cells (BMMCs) demonstrate that Stat5 is a critical regulator of mast cell function, survival, and proliferation. These effects are most profound when examining the major contribution that Stat5 makes to FcepsilonRI signaling. After IgE crosslinkage, mouse Stat5-deficient BMMCs exhibit significantly reduced degranulation and almost complete loss of inflammatory cytokine secretion. Our data illustrate Stat5 as a potentially important therapeutic target for mast cell-related diseases, which warrants an investigation into the mechanisms controlling Stat5 activation and its consequences in vivo. Our proposal is segregated into these two issues. Our Aim 1 is to determine how IgE-mediated signals activate Stat5 in mouse and human mast cells, and the role of Stat5 in mast cell function. By gaining understanding of the Stat5 signaling pathway, we can uncover how new therapeutic strategies may intervene in this process. Aim 2 is to determine the importance of Stat5 to the mast cell response in vivo. We will determine whether Stat5 activation is critical in mouse models of passive systemic anaphylaxis (PSA) and airway hyperresponsiveness (AHR). In doing so, we can demonstrate how Stat5 can influence the inflammatory response in vivo, which can suggest its feasibility as a therapeutic target. PUBLIC HEALTH RELEVANCE: Mast cells are associated with a number of inflammatory diseases. By studying how mast cells function, we can further our knowledge of how mast cells can influence disease and be able to uncover new therapeutic targets.