GPCR Kinase-5 in Inflammatory Bowel Disease

GPCR 激酶 5 在炎症性肠病中的作用

• 批准号: 8511928
• 负责人: Narayanan Parameswaran
• 金额: $ 21.09万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-10 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511928
• 关键词: Accounting; Affect; Biochemistry; Cardiovascular Diseases; Caring; Cell Culture Techniques; Cell Signaling Process; Cells; Clinical; Colitis; Data; Development; Disease; Drosophila genus; Drug Targeting; Family member; G Protein-Coupled Receptor Genes; G Protein-Coupled Receptor Kinase Family; G protein coupled receptor kinase; G-Protein-Coupled Receptors; GRK; Gene Expression; Gene Expression Regulation; Genotype; Goals; Health Care Costs; Histone Deacetylase; Human; Immune; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Knockout Mice; Laboratories; Lymphocyte; Mass Spectrum Analysis; Mediating; Medical; Modeling; Molecular; Mus; Nuclear; Pathogenesis; Phosphorylation; Phosphotransferases; Play; Primary Cell Cultures; Production; Protein-Serine-Threonine Kinases; Publishing; Receptor Signaling; Regulation; Role; Severities; Signal Pathway; Signal Transduction; Sodium Dextran Sulfate; Solid; T-Lymphocyte; Toll-like receptors; Tumor Necrosis Factor Receptor; United States; Zebrafish; base; cytokine; desensitization; human GRK5 protein; in vivo; insight; macrophage; member; mouse model; nervous system disorder; new therapeutic target; novel therapeutics; prevent; public health relevance; receptor; research study; toll-like receptor 4

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) affects more than 1.4 million people in the United States and accounts for more than $1.7 billion dollars in health care costs. IBD requires lifetime care and currently has no medical cure. Therefore, understanding the mechanisms involved in the pathogenesis of IBD is crucial for developing new therapeutic strategies to prevent or cure this inflammatory disease. Current studies demonstrate a crucial role for Toll-like receptors and NF?B signaling in the pathogenesis of intestinal inflammation. In this context, our laboratory recently identified GPCR kinase-5 to be an important regulator of NF?B signaling in immune cells, especially macrophages. G-protein coupled receptor (GPCR) kinases originally discovered for their role in GPCR phosphorylation, are now known to also mediate signal transduction from non-GPCRs via phosphorylation of cytosolic substrates. Of the seven GRK family members (serine/threonine kinases), studies from our laboratory and others demonstrate an evolutionarily conserved role for GPCR kinase-5 (GRK5) in the regulation of NF?B signaling pathway, as well as in the consequent inflammatory disease pathogenesis, especially mediated by TLRs. Our published and preliminary results demonstrate that GRK5 plays an important role in mouse models of inflammation including colitis. The objective of this proposal is to further expand on our findings and examine the role o GRK5 in mouse models of intestinal inflammation and determine the cellular and molecular mechanisms by which GRK5 modulates inflammatory bowel disease. To accomplish our objective, we will examine the following specific aims: 1. Determine the in vivo mechanisms by which GRK5 regulates inflammatory bowel disease; 2. Determine the cellular and molecular mechanisms by which GRK5 regulates intestinal inflammation. Results from these proposed studies in the short-term will provide important insights into the role of GRK5 in the pathogenesis of inflammatory bowel disease (IBD). In the long-term our studies will contribute to identifying new and novel therapeutic targets for inflammatory diseases including IBD.

描述(申请人提供)：炎症性肠病(IBD)在美国影响着140多万人，占医疗保健费用的17亿美元以上。IBD需要终生护理，目前还没有药物治愈。因此，了解IBD的发病机制对于开发预防或治愈这种炎症性疾病的新的治疗策略至关重要。目前的研究表明，Toll样受体和核因子？B信号在肠道炎症的发病机制中起着重要作用。在此背景下，我们的实验室最近鉴定出GPCRK-5是一种 免疫细胞，尤其是巨噬细胞中核因子B信号的重要调节因子。G蛋白偶联受体(GPCRK)最初被发现参与G蛋白偶联受体的磷酸化，现在已知也通过胞浆底物的磷酸化来介导非GPCRs的信号转导。在GRK家族的7个成员(丝氨酸/苏氨酸激酶)中，本实验室和其他人的研究表明，GRK5在调节NF？B信号通路以及随后的炎症性疾病发病机制中发挥着进化上的保守作用，特别是在TLRs的介导下。我们已发表的和初步的结果表明，GRK5在包括结肠炎在内的小鼠炎症模型中发挥着重要作用。这项建议的目的是进一步扩大我们的发现，研究GRK5在小鼠肠炎模型中的作用，并确定GRK5调控炎症性肠病的细胞和分子机制。为了实现我们的目标，我们将研究以下具体目标：1.确定GRK5调控炎症性肠病的体内机制；2.确定GRK5调控肠道炎症的细胞和分子机制。短期内这些拟议研究的结果将为GRK5在炎症性肠病(IBD)发病机制中的作用提供重要的见解。从长远来看，我们的研究将有助于确定包括IBD在内的炎症性疾病的新的治疗靶点。