权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of mast cells in obesity

肥大细胞在肥胖中的作用

基本信息

批准号：
7821268
负责人：
GUO-PING SHI
金额：
$ 42.51万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7821268
关键词：
Abdominal Aortic Aneurysm Adipocytes Adipose tissue Adult Affect Allergic inflammation Anti-Allergic Agents Aortic Aneurysm Atherosclerosis Biology Blood Vessels Body Weight Bone Marrow CCL2 gene Cathepsins Cell Adhesion Molecules Cells Chemotactic Factors Chymase Clinic Cromoglicic Acid Cysteine Protease Cytoplasmic Granules Development Diet Drug usage Effector Cell Exercise Extracellular Matrix Fatty acid glycerol esters Gelatinase B Genetic Growth Factor Homing Human Hypersensitivity In Vitro Incidence Individual Inflammatory Intraperitoneal Injections Knockout Mice Knowledge LTB4R gene Leptin Leukotriene B4 Lymphocyte Maintenance Mast Cell Stabilizer Mediator of activation protein Metabolic Diseases Mus Names Obese Mice Obesity Operative Surgical Procedures Participant Patients Peptide Hydrolases Phenotype Production Public Health Reagent Role Serum Social Problems Testing Therapeutic Intervention Time Tryptase Vascular Diseases Visceral Weight Gain Wild Type Mouse adipocyte differentiation adipokines allergic response angiogenesis asthmatic patient base chemokine chemokine receptor cytokine glucose metabolism glucose tolerance improved insulin sensitivity lipid biosynthesis macrophage mast cell mouse model protein degradation public health relevance receptor reconstitution research study

项目摘要

DESCRIPTION (provided by applicant): Mast cells are essential effector cells in the elicitation of the allergic responses by releasing cytoplasmic granules. Our recent studies suggest that mast cells participate in human pathobiology beyond allergic inflammation. Mast cell deficiency or pharmacological stabilization of mast cells reduces significantly the incidences of experimental atherosclerosis and abdominal aortic aneurysms in mice. As a close associated metabolic disorder of atherosclerosis and aortic aneurysms, obesity becomes not just an important scientific topic, but also a serious social problem worldwide. For the first time, we revealed accumulation of mast cells in adipose tissues from obese humans and mice. Using mast cell-deficient mouse model or anti-allergy mast cell stabilizer cromolyn, we demonstrated that mast cells are important player in obesity. Mast cell-deficient mice or those treated with cromolyn are significantly leaner than the control mice and show significant increase of glucose tolerance. Along with reduced body weight gain and increased glucose tolerance, serum levels of leptin, chemokine MCP-1, cytokine TNF-a, and obesity pertinent protease cathepsin S are also reduced in mast cell-deficient mice or those received cromolyn treatment. Although a mechanism by which mast cells contribute to obesity remains to be investigated, in vitro differentiated mast cells promote mouse pre-adipocyte differentiation. Thus, our central hypothesis is that mast cells produce pro-inflammatory cytokines and proteases to modulate the biology of adipose tissue and the extracellular matrix, thereby contributing to obesity, glucose tolerance and insulin sensitivity. Two specific aims are proposed: 1). To study the role of mast cells in body weight gain and glucose metabolism and to examine whether we can control the progression of obesity and/or reverse the phenotypes of pre-formed obesity in mice by regulating mast cell activations. 2). To identify which chemokine receptors that mast cells use for homing to the adipose tissues and to identify which of those common mast cell mediators contributes to obesity. Together, these lines of experiments should provide strong evidence of whether mast cells are required for obesity and mechanistic explanations of how mast cells might influence this common metabolic disorder. PUBLIC HEALTH RELEVANCE: Obesity is a serious public health problem that affects 30% of adults in the US. Although physical exercise and open surgery are used in the clinic to reduce the body weight, effective non-invasive therapy of obesity lacks. This proposal tests the hypothesis that pro-inflammatory mast cells are important participants of obesity, and examines thoroughly whether we can manage body weight gain by regulating mast cell activity.

描述（由申请方提供）：肥大细胞是通过释放胞质颗粒引发过敏反应的重要效应细胞。我们最近的研究表明，肥大细胞参与人类病理学过敏性炎症以外。肥大细胞缺乏或肥大细胞的药理学稳定显著降低小鼠实验性动脉粥样硬化和腹主动脉瘤的发生率。肥胖作为与动脉粥样硬化和主动脉瘤密切相关的代谢紊乱，不仅是一个重要的科学课题，也是一个严重的社会问题。我们首次揭示了肥胖的人和小鼠脂肪组织中肥大细胞的积累。使用肥大细胞缺陷小鼠模型或抗过敏肥大细胞稳定剂crologin，我们证明肥大细胞在肥胖中起重要作用。肥大细胞缺陷型小鼠或用克罗维汀治疗的小鼠比对照小鼠显著瘦，并且显示出葡萄糖耐量的显著增加。沿着降低的体重增加和增加的葡萄糖耐量，在肥大细胞缺陷小鼠或那些接受克罗维汀治疗的小鼠中，瘦素、趋化因子MCP-1、细胞因子TNF-α和肥胖相关蛋白酶组织蛋白酶S的血清水平也降低。虽然肥大细胞导致肥胖的机制仍有待研究，但体外分化的肥大细胞促进小鼠前脂肪细胞分化。因此，我们的中心假设是肥大细胞产生促炎细胞因子和蛋白酶来调节脂肪组织和细胞外基质的生物学，从而导致肥胖、葡萄糖耐量和胰岛素敏感性。提出了两个具体目标：1）。研究肥大细胞在体重增加和葡萄糖代谢中的作用，并检查我们是否可以通过调节肥大细胞活化来控制小鼠肥胖的进展和/或逆转预先形成的肥胖的表型。2）。为了确定哪些趋化因子受体，肥大细胞用于归巢到脂肪组织，并确定这些共同的肥大细胞介质有助于肥胖。总之，这些实验应该提供强有力的证据，证明肥大细胞是否是肥胖所必需的，并从机制上解释肥大细胞如何影响这种常见的代谢紊乱。肥胖是一个严重的公共卫生问题，影响着美国30%的成年人。虽然临床上采用了体育锻炼和开放手术来减轻体重，但缺乏有效的非侵入性治疗肥胖的方法。该提案测试了促炎性肥大细胞是肥胖的重要参与者的假设，并彻底检查了我们是否可以通过调节肥大细胞活性来管理体重增加。