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

Thrombospondin 1 in obesity associated inflammation and insulin resistance

血小板反应蛋白 1 在肥胖相关炎症和胰岛素抵抗中的作用

基本信息

批准号：
9273514
负责人：
Shuxia Wang
金额：
$ 28.88万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-20 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9273514
关键词：
Address Adipocytes Adipose tissue Binding CD36 gene Cardiovascular Diseases Cells Chemotactic Factors Chronic Crystallization Data Development Diet Disease Fibrosis Genotype High Fat Diet Human Hypertension In Vitro Infiltration Inflammation Inflammatory Injury Insulin Resistance Kidney Kidney Diseases Knockout Mice Lead Macrophage Activation Mediating Metabolic Modeling Molecular Mus N-terminal Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Peptides Phenotype Play Proteins Recruitment Activity Reporting Resistance development Rodent Roentgen Rays Role Signal Transduction Structure TLR4 gene Testing Thrombospondin 1 Tissues Visceral Wild Type Mouse adipokines base chemokine clinically relevant clinically significant design glucose tolerance human subject improved in vivo insulin mediators insulin sensitivity macrophage migration novel novel therapeutics obesity treatment prevent public health relevance receptor therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Increased accumulation of adipose tissue macrophages (ATMs) promotes obesity-associated chronic inflammation and insulin resistance. Although there have been some advances in the study of ATMs in obese condition, the mechanisms underlying ATMs recruitment and activation remain to be determined. Thrombospondin 1 (TSP1) has been identified to be an adipokine and its expression levels correlate positively with human obesity, adipose tissue inflammation and insulin resistance. By using TSP1 deficient mice, preliminary studies revealed a novel role for TSP1 in stimulating macrophage recruitment and activation in adipose tissue that contributes to inflammation and insulin resistance resulting from high fat diet-induced obesity (DIO). Moreover, TSP1 promoting macrophage migration and activation is through the N-terminal domain and the type 1 repeats to interact with receptors LRP1 and CD36, respectively. Blocking the interactions of TSP1/LRP1 and TSP1/CD36 inhibited TSP1 stimulation of macrophage function. Based on these data, we hypothesize that blockade of the stimulatory effect of TSP1 on macrophage function prevents/ameliorates obesity-associated inflammation and insulin resistance. To test this hypothesis, in Aim 1, tissue specific TSP1 knockout mice will be used to definitively answer the question of whether adipocyte-derived TSP1 serves as a primary chemokine to stimulate macrophage accumulation in adipose tissue and promotes the development of obesity-associated inflammation and insulin resistance. In Aim 2, utilizing the identified stimulatory domains on TSP1 as targets, based on their available x-ray crystal structures, new decoy peptides will be designed by structure-based computational design strategy. The inhibitory effect of decoy peptides on TSP1stimulation of macrophage function will be tested. In Aim 3, whether blocking of TSP1/CD36 interaction can prevent/ameliorate obesity-associated inflammation and insulin resistance in vivo will be tested. Together, these proposed studies may lead to novel therapeutics for obesity-induced insulin resistance and metabolic complications, and therefore, have significant clinical relevance.

描述(由申请人提供)：脂肪组织巨噬细胞(ATM)的积累增加会促进肥胖相关的慢性炎症和胰岛素抵抗。虽然在肥胖状态下ATM的研究已经取得了一些进展，但ATM招募和激活的机制仍有待确定。凝血酶敏感蛋白1(TSP1)是一种脂肪因子，其表达水平与人类肥胖、脂肪组织炎症和胰岛素抵抗呈正相关。通过使用TSP1缺陷小鼠，初步研究揭示了TSP1在刺激脂肪组织中巨噬细胞募集和激活方面的新作用，这有助于高脂饮食诱导肥胖(DIO)引起的炎症和胰岛素抵抗。此外，TSP1促进巨噬细胞的迁移和激活是通过N端结构域和类型1重复分别与受体LRP1和CD36。阻断TSP1/LRP1和TSP1/CD36的相互作用可抑制TSP1对巨噬细胞功能的刺激。基于这些数据，我们假设阻断TSP1对巨噬细胞功能的刺激作用可以预防/改善肥胖相关的炎症和胰岛素抵抗。为了验证这一假设，在目标1中，组织特异性TSP1基因敲除小鼠将被用于明确回答脂肪细胞来源的TSP1是否作为主要趋化因子刺激脂肪组织中巨噬细胞聚集，并促进肥胖相关炎症和胰岛素抵抗的发展。在目标2中，以已确定的TSP1上的刺激结构域为靶点，根据其已有的X射线晶体结构，采用基于结构的计算设计策略设计新的诱饵多肽。将测试诱骗多肽对TSP1刺激巨噬细胞功能的抑制作用。在目标3中，将测试阻断TSP1/CD36相互作用是否能够在体内预防/改善肥胖相关的炎症和胰岛素抵抗。总之，这些拟议的研究可能会导致肥胖引起的胰岛素抵抗和代谢并发症的新疗法，因此，具有重要的临床意义。