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：
8757738
负责人：
Shuxia Wang
金额：
$ 30.91万
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 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8757738
关键词：
Address Adipocytes Adipose tissue Binding CD36 gene Cardiovascular Diseases Cells Chemotactic Factors Chronic Data Development Diet Disease Fatty acid glycerol esters Fibrosis Genotype Human Hypertension In Vitro Infiltration Inflammation Inflammatory Injury Insulin Resistance Kidney Kidney Diseases Knockout Mice Lead Macrophage Activation Mediating Mediator of activation protein Metabolic Modeling Molecular Mus N-terminal Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Peptides Phenotype Play Proteins Reporting Resistance development Rodent Role Signal Transduction Structure TLR4 gene Testing Thrombospondin 1 Tissues Visceral Wild Type Mouse Work base chemokine clinically relevant clinically significant design glucose tolerance human subject improved in vivo 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）的积累增加可促进与肥胖相关的慢性炎症和胰岛素抵抗。尽管在肥胖状态下对ATM的研究已经取得了一些进步，但ATM募集和激活的基础机制仍有待确定。血小板传播1（TSP1）已被确定为脂肪因子，其表达水平与人肥胖，脂肪组织炎症和胰岛素抵抗呈正相关。通过使用TSP1缺乏小鼠，初步研究揭示了TSP1在刺激巨噬细胞募集和脂肪组织中激活中的新作用，从而导致高脂肪饮食诱导的肥胖（DIO）导致炎症和胰岛素抵抗。此外，促进巨噬细胞迁移和激活的TSP1分别通过N末端结构域和1型重复与受体LRP1和CD36相互作用。阻止TSP1/LRP1和TSP1/CD36的相互作用抑制了TSP1刺激巨噬细胞功能。基于这些数据，我们假设TSP1对巨噬细胞功能的刺激作用的封锁可防止/缓解与肥胖相关的炎症和胰岛素抵抗。为了检验该假设，在AIM 1中，将使用组织特异性TSP1敲除小鼠来确定回答脂肪细胞衍生的TSP1是否用作刺激脂肪组织中巨噬细胞积累的主要趋化因子并促进肥胖相关炎症和胰岛素抵抗的发展。在AIM 2中，利用TSP1上确定的刺激域作为目标，基于其可用的X射线晶体结构，将通过基于结构的计算设计策略设计新的诱饵肽。诱饵肽对巨噬细胞功能的TSP1刺激的抑制作用将被测试。在AIM 3中，将测试TSP1/CD36相互作用的阻断是否可以预防/改善肥胖相关的炎症和体内胰岛素抵抗。这些提出的研究一起可能导致肥胖诱导的胰岛素抵抗和代谢并发症的新型治疗，因此具有显着的临床相关性。