CD47 as a therapeutic target for obesity

CD47作为肥胖症的治疗靶点

基本信息

批准号：
10608932
负责人：
Shuxia Wang
金额：
--
依托单位：
VA MEDICAL CENTER - LEXINGTON, KY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-10-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10608932
关键词：
Adipocytes Adipose tissue Animal Model Animals Antisense Oligonucleotides Attenuated Body Weight Body fat Body mass index Brown Fat CD47 gene Carnitine Palmitoyltransferase I Cell Line Cell membrane Cell physiology Cells Complex Cyclic AMP Cyclic GMP Data Development Diet Eating Energy Intake Energy Metabolism Exhibits Fatty acid glycerol esters Functional disorder Genes Genotype High Fat Diet Homeostasis Human Genome In Vitro Insulin Resistance Investigation Knockout Mice Mediating Membrane Metabolic Mitochondria Modeling Molecular Mus Nerve Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Obesity Epidemic Resistance Respiration Risk Factors Rodent Rodent Model Role Signal Pathway Signal Transduction Single Nucleotide Polymorphism System Testing Therapeutic Thermogenesis Tissues Wild Type Mouse Work adipocyte differentiation blood glucose regulation clinically significant combat comorbidity diet-induced obesity fatty liver disease genome-wide analysis human subject immune function improved in vivo knock-down lipid biosynthesis lipid metabolism mouse model novel novel therapeutic intervention obesity development obesity genetics obesity treatment oxidation prevent receptor therapeutic target tool

项目摘要

Brown adipose tissue (BAT) dissipates energy through UCP1-mediated uncoupled respiration and its activation may represent a therapeutic strategy to combat obesity. Preliminary studies identified a novel role of CD47 in regulating BAT function and its contribution to energy homeostasis and the development of obesity. CD47, a ubiquitously expressed cell membrane receptor implicated in self-recognition and immune function, was upregulated in adipose tissue from obese animals. Moreover, CD47 deficiency protected mice from diet- induced obesity (DIO) through activation of BAT function (e.g. enhanced mitochondria uncoupling and heat production) and increased energy expenditure. These data suggest that CD47 is a negative regulator of BAT activity. Therefore, inhibition of CD47 signaling might be a novel anti-obesity strategy, which is further supported by a recent human genome-wide study showing the association of single-nucleotide polymorphisms in CD47 gene with body weight and BMI. In this proposal the mechanisms by which CD47 downregulates brown fat cell function will be determined in Aim 1. The contribution of brown adipocyte specific CD47 deficiency on obesity development will be determined in Aim 2. Whether inhibition of CD47 signaling by CD47- antisense oligo (ASO) treatment activates BAT and prevents/ameliorates obesity development in animal models will be determined in Aim 3. These studies will not only provide novel information on the mechanisms by which CD47 down-regulates brown fat function and its contribution to energy homeostasis and the development of obesity, but also test the anti-obesity potential of a CD47-ASO in obese mouse models. Therefore these studies have clinical significance.

棕色脂肪组织（BAT）通过UCP1介导的未偶联呼吸及其激活消散能量可以代表对抗肥胖症的治疗策略。初步研究确定了CD47的新作用在调节蝙蝠功能及其对能量稳态的贡献和肥胖的发展。 CD47，一种普遍表达的细胞膜受体，涉及自识别和免疫功能，在肥胖动物的脂肪组织中被上调。此外，CD47缺乏保护小鼠免受饮食的影响 - 通过激活BAT功能引起的肥胖（DIO）（例如，线粒体解偶联和热量增强生产）和增加的能源消耗。这些数据表明CD47是BAT的负调节器活动。因此，抑制CD47信号可能是一种新型的抗肥胖策略，这是进一步的在最新的人类基因组研究的支持下，显示了单核苷酸多态性的关联在具有体重和BMI的CD47基因中。在此提案中，CD47下调的机制棕色脂肪细胞功能将在AIM 1中确定。棕色脂肪细胞特异性CD47的贡献肥胖发展的缺乏将在目标2中确定。是否通过CD47-抑制CD47信号传导反义寡醇（ASO）处理可激活蝙蝠并防止/改善动物的肥胖模型将在AIM 3中确定。这些研究不仅将提供有关机制的新信息 CD47下调棕色脂肪功能及其对能量稳态的贡献肥胖的发展，但还测试了肥胖小鼠模型中CD47-ASO的抗肥胖潜力。因此，这些研究具有临床意义。