Mast Cell Responses to Insulin

肥大细胞对胰岛素的反应

• 批准号: 8880060
• 负责人: HELEN C TURNER
• 金额: $ 43.12万
• 依托单位: CHAMINADE UNIVERSITY OF HONOLULU
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8880060
• 关键词: Abdomen; Address; Adipose tissue; Affect; Antigens; Biochemical; Biochemistry; Biogenesis; Calcium; Cell Differentiation process; Cell physiology; Cells; Chemicals; Chronic; Complement; Complex; Cytoplasmic Granules; Data; Deposition; Development; Drug or chemical Tissue Distribution; Epidemic; Epidemiologic Studies; Functional disorder; Generations; Genes; Genetic Transcription; Health; Healthcare; Heterogeneity; Histamine; Hyperinsulinism; Immune system; Immunization; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Receptor; Laboratories; Leukotriene C4; Lipids; Liver; Measures; Mediating; Metabolic; Metabolic syndrome; Non-Insulin-Dependent Diabetes Mellitus; Normal Cell; Obesity; Operative Surgical Procedures; Organelles; Outcome; Pancreatectomy; Paper; Pathology; Patients; Pattern; Peptide Hydrolases; Phenotype; Population; Protein Biosynthesis; Proteomics; Publishing; Quality of life; Regulation; Relative (related person); Resources; Role; Second Messenger Systems; Secretory Vesicles; Shapes; Signal Pathway; Signal Transduction; Skeletal Muscle; Stimulus; Structure of beta Cell of islet; Tissues; Work; base; immunopathology; in vivo; insight; insulin signaling; interest; lipid biosynthesis; lipid mediator; loss of function; mast cell; novel; outcome forecast; programs; promoter; protective effect; public health relevance; response; second messenger; socioeconomics; subcutaneous; synthetic enzyme

 DESCRIPTION (provided by applicant): Obesity and the metabolic syndrome affect the health of millions of individuals. Systemic hyperinsulinemia is associated with elevated adiposity and the pancreatic beta cell dysfunction that precedes the development of Type II diabetes, but is an understudied pathological state in its own right The central premise of our current work is that the systemic effects of hyperinsulinemia extend to the regulation of lipid body (LB) numbers in pro-inflammatory cells, with concomitant effects on cellular function and consequences for our understanding of the immunological impact of hyperinsulinemia. Insulin's regulation of mast cells has been speculated upon since the 1960s. Mast cells (MC) are professional pro-inflammatory cells that express insulin receptors and contain cytosolic LB and, while not previously recognized as targets for insulin signaling, these LB are specialized reservoirs of precursors for pro-inflammatory lipid mediators. Our recently published data establish that LB numbers in mast cells are dynamically regulated under in vitro, ex vivo and in vivo conditions of hyperinsulinemia. This insulin-driven hyper-accumulation of LB results in gain- and loss- of-function for the mast cell, enhancing antigen-driven release of bioactive lipids such as leukotriene C4 and, remarkably, compromising antigen-induced histamine and matrix-active protease release from secretory granules (SG). Our data provide a possible mechanism for the documented protective effects of insulin deficiency on mast cell-driven pathologies, suggest that insulin regulates mast cell functional phenotype, and establish mast cell LB as central arbiters of the impact of metabolic dysfunction on pro-inflammatory responses. Our findings raise new questions that will be addressed in three Specific Aims: Specific Aim 1. Does insulin transcriptionally program the LB:SG ratio in mast cells? We hypothesize that insulin regulates the ratio of LB and SG in these cells. Specific Aim 2. Are the stored and released mast cell LB lipidomes remodeled in response to cellular activation? We hypothesize that the expanded pool of LB present in insulin-exposed mast cells provides precursors for bioactive lipid synthesis, which modifies mast cell activation outcomes. Specific Aim 3. Are there important non-lipid storage roles for MC LB? We hypothesize that by acting as previously undefined calcium storage compartments, LB provide non-lipid storage-related functions in mast cells that are dysregulated when the LB population expands under hyperinsulinemic conditions. We predict that this study will reveal (1) that insulin is determinant of the relative abundance of SG and LB, and contributes to the generation of mast cell heterogeneity in vivo; (2) the functional contribution made by mast cell LB to inflammation; (3) LB as novel Ca2+ sinks that alter fundamental patterns in second messenger signaling following antigen stimulation of MC. These data will provide evidence that the systemic effects of hyperinsulinemia extend to regulation of LB numbers in pro-inflammatory cells, with concomitant effects on cellular function and cellular signaling. We will contribute to a new understanding of the immuno-pathological consequences of systemic hyperinsulinemia.

 描述(申请人提供)：肥胖和代谢综合征影响数百万人的健康。全身性高胰岛素血症与脂肪增加和胰岛β细胞功能障碍有关，后者是II型糖尿病发展的先兆，但本身是一种未被研究的病理状态。我们目前工作的中心前提是，高胰岛素血症的全身性影响延伸到促炎症细胞中的脂体(Lb)数量的调节，伴随着对细胞功能的影响以及对我们理解高胰岛素血症的免疫学影响的后果。自20世纪60年代以来，人们就一直在推测胰岛素对肥大细胞的调节。肥大细胞(MC)是专业的促炎细胞，表达胰岛素受体，并含有胞浆中的Lb，虽然以前没有被认为是胰岛素信号的靶标，但这些Lb是促炎脂质介质的前体的专门储存库。我们最近发表的数据表明，肥大细胞中的LB值在体外、体外和体内的高胰岛素血症条件下都是动态调节的。这种胰岛素驱动的超积累导致肥大细胞功能的增加和丧失，促进了抗原驱动的生物活性脂质的释放，如白三烯C4，并显著地影响了抗原诱导的组胺和分泌颗粒(SG)的基质活性蛋白酶的释放。我们的数据为胰岛素缺乏对肥大细胞驱动的病理的保护作用提供了一个可能的机制，提示胰岛素调节肥大细胞的功能表型，并建立肥大细胞Lb作为肥大细胞的中央仲裁因子。 代谢功能障碍对促炎反应的影响。我们的发现提出了新的问题，这些问题将在三个特定的目标中得到解决：特定的目标1。胰岛素是否在转录上编程肥大细胞中的LB/SG比率？我们假设胰岛素调节这些细胞中的LB和SG的比例。特定目的2.储存和释放的肥大细胞LB型脂质体是否因细胞激活而改变？我们假设，胰岛素暴露的肥大细胞中存在的扩大的LB池为生物活性脂肪合成提供了前体，而生物活性脂肪合成改变了肥大细胞的激活结果。具体目标3：MC LB是否具有重要的非脂类储存作用？我们假设，通过充当先前未定义的钙存储隔间，Lb在肥大细胞中提供与脂质存储相关的功能，当Lb群体在高胰岛素条件下扩张时，肥大细胞的调节是失调的。我们预测，这项研究将揭示(1)胰岛素是SG和Lb相对丰度的决定因素， 并有助于体内肥大细胞异质性的产生；(2)肥大细胞对炎症的功能贡献；(3)作为新的钙离子下沉，在MC抗原刺激后改变第二信使信号的基本模式的Lb。这些数据将提供证据，证明高胰岛素血症的全身性影响延伸到调节促炎细胞中的LB值，并伴随着对细胞功能和细胞信号的影响。我们将有助于对全身性高胰岛素血症免疫病理后果的新理解。