Mast Cell S1P Receptor2 in the initiation and progression of chronic inflammation

肥大细胞S1P受体2在慢性炎症的发生和进展中的作用

• 批准号: 8730283
• 负责人: CAROLE A OSKERITZIAN
• 金额: $ 32.45万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-27 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8730283
• 关键词: Acute; Affinity; Allergens; Allergic; Allergic inflammation; Angiogenic Factor; Binding; Blood Vessels; Cell Count; Cells; Chronic; Data; Defect; Development; Disease; Disease Progression; Disease Resistance; Drug resistance; Early Intervention; Edema; Event; H218 Protein; Health Care Costs; Histamine; IgE; IgE Receptors; Individual; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Lead; Link; Lipids; Lung; Lung Inflammation; Mediating; Mediator of activation protein; Molecular Genetics; Mus; Nature; Pathway interactions; Phase; Play; Pneumonia; Process; Production; Regulation; Regulatory Pathway; Role; Signal Pathway; Signal Transduction; Sphingolipids; Sphingosine-1-Phosphate Receptor; Stat3 protein; Surface; Testing; Tissues; Treatment Failure; Vascular Endothelial Growth Factor A; angiogenesis; chemokine; crosslink; cytokine; in vivo; in vivo Model; innovation; mast cell; mouse model; neutralizing monoclonal antibodies; novel; prevent; receptor; sphingosine 1-phosphate; sphingosine kinase; transcription factor

DESCRIPTION (provided by applicant): Chronic inflammation is often the result of treatment failure and drug resistance. Located around blood vessels, mast cells are primary responders in inflammation by releasing pre-formed as well as de novo synthesized various inflammatory mediators, including histamine, cytokines, and chemokines upon allergen cross-linking of high affinity receptors for IgE (Fc?RI). In addition, activated mast cells can release the sphingolipid metabolite sphingosine-1-phosphate (S1P), generated upon sphingosine kinase (SphK) activation. Secreted S1P can bind to its own receptors, such as the type 2 receptor (S1P2) expressed on mast cells. Several mouse models of chronic inflammatory disorders have established an early increase in mast cell number in inflammatory foci, suggesting their early intervention in the process. We have shown that mast cell S1P2 is essential to the early events associated with acute signs of allergic inflammation, among which edema surrounding the blood vessels in the lungs. Edema promotes subsequent recruitment of inflammatory cells, also favored by increased number of blood vessels, features commonly observed in chronic inflammation. We are proposing to study the contribution of mast cell-expressed S1P2 in the disease progression using mouse models of mast cell-mediated pulmonary inflammation and define how it could lead to persistent inflammation. Using pharmacological, molecular and genetic approaches, we have discovered a new signaling pathway linking S1P2 to Stat3 transcription factor and how disrupting this pathway may potentially abrogate aspects of remodeling observed in chronic inflammation. The objectives of this application are: to establish the role of S1P2 in initiating inflammatory cell infiltration and propagating inflammation~ to elucidate the newly identified signaling pathway and its relevance to remodeling~ to develop in vivo models targeting the mast cell/S1P/ S1P2 axis in an attempt to prevent features associated with chronic inflammatory disorders. Since targeting individual mediators has failed to prevent sustained inflammation, we anticipate our proposed studies will lead to a better understanding of its underlying mechanisms and pave the way for more mechanistically tailored therapies targeting local regulatory pathways in inflammation with a central role for mast cell expressed S1P2.

描述（由申请人提供）：慢性炎症通常是治疗失败和耐药性的结果。肥大细胞位于血管周围，是炎症的主要反应者，通过与 IgE (Fc?RI) 高亲和力受体发生过敏原交联，释放预先形成的以及从头合成的各种炎症介质，包括组胺、细胞因子和趋化因子。此外，激活的肥大细胞可以释放鞘氨醇激酶 (SphK) 激活时产生的鞘脂代谢物 1-磷酸鞘氨醇 (S1P)。分泌的 S1P 可以与其自身的受体结合，例如肥大细胞上表达的 2 型受体 (S1P2)。几种慢性炎症性疾病的小鼠模型已经建立了炎症灶中肥大细胞数量的早期增加，表明它们在此过程中进行了早期干预。我们已经证明，肥大细胞 S1P2 对于与过敏性炎症急性症状相关的早期事件至关重要，其中包括肺部血管周围的水肿。水肿促进随后炎症细胞的募集，血管数量增加也有利于炎症细胞的聚集，这是慢性炎症中常见的特征。我们提议使用肥大细胞介导的肺部炎症小鼠模型来研究肥大细胞表达的 S1P2 在疾病进展中的作用，并确定它如何导致持续性炎症。 利用药理学、分子和遗传学方法，我们发现了一条连接 S1P2 和 Stat3 转录因子的新信号通路，以及破坏该通路如何可能消除在慢性炎症中观察到的重塑的各个方面。本申请的目的是：确定 S1P2 在启动炎症细胞浸润和传播炎症中的作用~阐明新发现的信号通路及其与重塑的相关性~开发针对肥大细胞/S1P/S1P2 轴的体内模型试图预防与慢性炎症性疾病相关的特征。由于针对个体介质未能预防持续性炎症，我们预计我们提出的研究将有助于更好地了解其潜在机制，并为针对炎症局部调节途径（以肥大细胞表达的 S1P2 发挥核心作用）的更多机制定制疗法铺平道路。 。