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Pref-1 receptor: Identification and characterization in inhibiting adipogenesis

Pref-1 受体：抑制脂肪生成的鉴定和表征

基本信息

批准号：
10241438
负责人：
Hei Sook Sul
金额：
$ 37.97万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-13 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241438
关键词：
Ablation Adipocytes Adipose tissue Affinity Binding Biochemical Biological Biological Assay CCAAT-enhancer-binding protein-delta Cell membrane Cells Chemicals Chemistry Cleaved cell Cultured Cells Development Diabetes Mellitus Diazomethane Disease Management EGF gene Esters Extracellular Domain Fatty acid glycerol esters Future Gene Expression Glucose Goals Health Heterodimerization Homeostasis IRAK1 gene In Situ In Vitro Insulin Knockout Mice Ligands Lipodystrophy MEKs Maintenance Membrane Glycoproteins Membrane Proteins Metabolic syndrome Methods Molecular Morphology Mus Non-Insulin-Dependent Diabetes Mellitus Nude Mice Obesity Peptides Population Recombinants Research Signal Pathway Signal Transduction Site Testing Weight adipocyte differentiation autocrine base diabetes control experimental study improved in vivo inhibitor/antagonist lipid biosynthesis loss of function mouse model neutralizing antibody overexpression paracrine preadipocyte factor 1 prevent progenitor receptor receptor binding therapeutic target

项目摘要

Pref-1 (Preadipocyte factor-1) is a widely used preadipocyte marker that we originally cloned and identified. Pref-1 is expressed in preadipocytes, downregulated during adipocyte differentiation, and is absent in adipocytes. Pref-1 is synthesized as a plasma membrane protein with 6 EGF-repeats in the extracellular domain. Pref-1 ectodomain is cleaved by TACE to generate the biologically active soluble Pref-1. Gain- and loss-of function studies in cultured cells, as well as in mice in vivo showed Inhibition of adipogenesis by Pref-1 in autocrine/paracrine manner. Thus, whereas Pref-1ablated mice have higher adipose tissue mass, Pref-1 overexpression in adipose tissue causes partial lipodystrophy with ectopic fat storage. Pref-1 activates MEK/ERK to induce Sox9, which in turn suppresses C/EBPb and C/EBPd, to inhibit adipocyte differentiation. However, the Pref-1 receptor at the plasma membrane that initiates Pref-1 signaling is yet to be identified. By using recently developed diazirine photo-reactive linker combined with robust NHS-ester chemistry in situ, the putative plasma membrane receptor for Pref-1 has recently been identified. The goal of this research is to firmly establish and characterize the Pref-1 receptor which is the most proximal and critical component of Pref-1 signaling and to study the downstream components to inhibit adipocyte differentiation. To accomplish this goal, biochemical, cellular and molecular approaches as well as gain- and loss-of function studies in vitro and in vivo will be taken. In the long run, elucidating mechanisms underlying Pref-1 binding to the Pref-1 receptor and its downstream signaling pathway will help to develop strategies to control adipogenesis.

Pref-1 （Preadipocyte factor-1）是我们最初克隆并鉴定的广泛应用的前脂肪细胞标志物。Pref-1在前脂肪细胞中表达，在脂肪细胞分化过程中下调，在脂肪细胞中不存在。Pref-1是一种质膜蛋白，在细胞外区域有6个egf重复序列。通过TACE裂解Pref-1外结构域，生成具有生物活性的可溶性Pref-1。在培养细胞和小鼠体内进行的功能增益和功能丧失研究表明，Pref-1以自分泌/旁分泌方式抑制脂肪生成。因此，尽管Pref-1消融的小鼠具有更高的脂肪组织质量，但脂肪组织中Pref-1的过度表达导致部分脂肪营养不良并伴有异位脂肪储存。Pref-1激活MEK/ERK诱导Sox9，进而抑制C/EBPb和C/EBPd，从而抑制脂肪细胞分化。然而，质膜上启动Pref-1信号传导的Pref-1受体尚未被确定。通过使用最近开发的重氮嘧啶光反应连接剂结合强大的nhs -酯原位化学反应，最近已经确定了Pref-1的推定质膜受体。本研究的目的是巩固和表征Pref-1信号传导最近和最关键的成分Pref-1受体，并研究抑制脂肪细胞分化的下游成分。为了实现这一目标，将采取生物化学，细胞和分子方法以及体外和体内功能的增益和损失研究。从长远来看，阐明Pref-1与Pref-1受体结合的机制及其下游信号通路将有助于制定控制脂肪形成的策略。