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

基本信息

批准号：
8859955
负责人：
CAROLE A OSKERITZIAN
金额：
$ 34.53万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-27 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8859955
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 Fc Receptor 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 Process Production Pulmonary Inflammation 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 genetic approach in vivo in vivo Model innovation mast cell mouse model neutralizing monoclonal antibodies novel prevent receptor sphingosine 1-phosphate sphingosine kinase targeted treatment transcription factor

项目摘要

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，是炎症中的主要反应者，通过释放预先形成的和从头合成的各种炎症介质，包括组胺，细胞因子和趋化因子和趋化因子在高过敏原亲和力受体的过敏蛋白交联IgE（FC？RI）上。此外，活化的肥大细胞可以释放在鞘氨醇激酶（SPHK）激活上产生的鞘脂代谢物鞘氨酸1-磷酸（S1P）。分泌的S1P可以与其自身的受体结合，例如在肥大细胞上表达的2型受体（S1P2）。慢性炎症性疾病的几种小鼠模型已经建立了炎症灶中肥大细胞数的早期增加，这表明它们在此过程中的早期干预。我们已经表明，肥大细胞S1P2对于与过敏性炎症的急性迹象相关的早期事件至关重要，其中肺部血管周围的水肿。水肿促进了随后的炎症细胞的募集，也受到血管数量增加的青睐，这在慢性炎症中通常观察到。我们建议使用肥大细胞介导的肺部炎症的小鼠模型研究肥大细胞表达的S1P2在疾病进展中的贡献，并定义如何导致持续性炎症。使用药理学，分子和遗传方法，我们发现了一种将S1P2与STAT3转录因子联系起来的新信号通路，以及该途径的破坏如何有可能消除慢性炎症中观察到的重塑的各个方面。该应用的目的是：确定S1P2在启动炎症细胞浸润和传播炎症中的作用，以阐明新近鉴定的信号通路及其与重塑〜的相关性，以开发针对MAST/ S1P/ S1P2 AXIS的体内模型，以防止与炎症性疾病相关的特征。由于针对单个介体的针对性介导者无法防止持续的炎症，因此我们预计我们的拟议研究将更好地理解其潜在机制，并为针对炎症中局部调节途径的更机械量身定制的疗法铺平了道路，其中心作用具有媒介细胞表达S1P2的核心作用。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mast cell plasticity and sphingosine-1-phosphate in immunity, inflammation and cancer.

DOI：
10.1016/j.molimm.2014.03.018
发表时间：
2015-01
期刊：
Molecular immunology
影响因子：
3.6
作者：
Oskeritzian CA
通讯作者：
Oskeritzian CA

Methods for Analyzing Sphingosine-1-Phosphate Signaling in Human and Mouse Primary Mast Cells.

分析人和小鼠原代肥大细胞中 1-磷酸鞘氨醇信号传导的方法。

DOI：
10.1007/7651_2017_42
发表时间：
2018
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Chumanevich,AlenaP;Wedman,PiperA;Oskeritzian,CaroleA
通讯作者：
Oskeritzian,CaroleA

Sphingosine-1 Phosphate: A New Modulator of Immune Plasticity in the Tumor Microenvironment.

DOI：
10.3389/fonc.2016.00218
发表时间：
2016
期刊：
Frontiers in oncology
影响因子：
4.7
作者：
Rodriguez YI;Campos LE;Castro MG;Aladhami A;Oskeritzian CA;Alvarez SE
通讯作者：
Alvarez SE

A New Image Analysis Method Based on Morphometric and Fractal Parameters for Rapid Evaluation of In Situ Mammalian Mast Cell Status.

DOI：
10.1017/s1431927615015342
发表时间：
2015-12
期刊：
MICROSCOPY AND MICROANALYSIS
影响因子：
2.8
作者：
Wedman, Piper;Aladhami, Ahmed;Beste, Mary;Edwards, Morgan K.;Chumanevich, Alena;Fuseler, John W.;Oskeritzian, Carole A.
通讯作者：
Oskeritzian, Carole A.

Sphingosine-1-Phosphate/Sphingosine-1-Phosphate Receptor 2 Axis Can Promote Mouse and Human Primary Mast Cell Angiogenic Potential through Upregulation of Vascular Endothelial Growth Factor-A and Matrix Metalloproteinase-2.