The characterization of Cela2a, a novel disease gene for metabolic syndrome in health and diseases

Cela2a（一种健康和疾病代谢综合征的新型疾病基因）的表征

基本信息

批准号：
10681049
负责人：
Arya Mani
金额：
$ 69.66万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681049
关键词：
Acinar Cell Adipose tissue Animal Model Applications Grants Atherosclerosis Attenuated Autologous Transplantation Binding Blood Blood Platelets Blood Pressure Body mass index Carrier Proteins Cell membrane Cells Circulation Closure by clamp Cyclic AMP-Dependent Protein Kinases Diabetes Mellitus Disease Disease Pathway Eating Elastases Enzymes Epithelial Cells Exhibits Exocrine pancreas Family Fatty Acids Fatty Liver G-Protein-Coupled Receptors General Population Genes Genets Glucose Goals Health Hepatic Homeostasis Human Hyperglycemia Hyperglycemic Mice Hyperinsulinism Hypertension Hypertriglyceridemia Impairment Individual Insulin Insulin Resistance Insulin deficiency Islets of Langerhans Knockout Mice LDL Cholesterol Lipoproteins Ligands Lipids Lipolysis Liver Membrane Membrane Proteins Metabolic Metabolic syndrome Molecular Molecular Mechanisms of Action Mus Muscle Mutation Non-Insulin-Dependent Diabetes Mellitus PIK3CG gene Pancreas Pancreatectomy Pancreatic Elastase Pathway interactions Patients Phenocopy Phenotype Physiological Plasma Platelet aggregation Proteins Proteolysis Proto-Oncogene Proteins c-akt Regulation Resistance Risk Factors Role Sequence Analysis Serine Protease Signal Transduction Site Systems Biology Techniques Therapeutic Tissues Total Pancreatectomy Triglycerides Variant Work blood glucose regulation blood pressure regulation chymotrypsin cohort early onset euglycemia exome gain of function genome wide association study glucose metabolism human disease human subject in vitro activity in vivo insulin secretion insulin sensitivity intestinal epithelium islet kindred lipid biosynthesis lipid metabolism loss of function mutation metabolic phenotype mouse model mutant mutation carrier new therapeutic target non-alcoholic fatty liver disease novel response segregation skeletal tissue therapeutic target trait uptake

项目摘要

Molecular mechanisms that regulate insulin resistance and its progression to type2 diabetes (T2D) are not understood and might reveal a therapeutic opportunity to reduce the burden of T2D. We recently identified causative loss-of-function mutations in the CELA2A gene (Esteghamat & Mani, Nat. Genet. 2019), which encodes the pancreatic elastase Chymotrypsin-like ELAstase 2A in kindreds with extreme phenotypes of metabolic syndrome, type 2 diabetes, and early-onset atherosclerosis. Interestingly, the genome-wide association studies have also shown a strong association between common variants in the CELA2A gene and blood pressure, LDL cholesterol and BMI, underscoring its role in the disease of the general population. Although only known for its function as a pancreatic exocrine enzyme, we found it to be a circulating protein that is expressed in the extrapancreatic tissues, including gut. Its plasma levels rise after each meal in parallel to plasma insulin levels in healthy humans. Our characterization of CELA2A functions revealed its ability to trigger insulin secretion and sensitivity. In contrast, the catalytically inactive mutant CELA2A proteins found in the cohort increased platelet aggregation and reduced insulin sensitivity. Mechanistically, CELA2A was found to proteolytically cleave GPCRs such as PAR2 and induce PAR2-dependent activation of AMPK, while mutant CELA2As trigger different PAR2-dependent pathways, resulting in increased ERK and reduced AMPK activation. Thus, CELA2A appears to be an endogenous ligand of PAR2, a GPCR that has been implicated in the regulation of glucose homeostasis. These functions underscore CELA2A’s role as a novel risk factor and an attractive therapeutic target for the treatment of T2D. We will investigate the physiological functions of CELA2A and explore its molecular mechanisms of action in glucose homeostasis in global, acinar cell- and gut-specific Cela2a knockout mice, with a focus PAR2-dependent pathways. Cela2a KO mice are ideal for this goal as they show impaired insulin sensitivity and increased hepatic and plasma triglycerides that match the phenotypes of humans.

调节胰岛素抵抗及其发展为2型糖尿病（T2D）的分子机制不是了解并可能揭示了减少T2D燃烧的治疗机会。我们最近确定了 CELA2A基因中的功能丧失突变（Esteghamat＆Mani，Nat。Genet。2019），它用极端表型中的胰腺胰凝乳素样弹性酶2a编码代谢综合征，2型糖尿病和早期性动脉粥样硬化。有趣的是，全基因组关联研究还表明，Cela2a基因中的常见变体与血压，LDL胆固醇和BMI强调了其在普通人群疾病中的作用。尽管仅以其功能作为胰腺外分泌酶而闻名，但我们发现它是循环蛋白这在包括肠道在内的胰腺外组织中表达。每顿饭并联后的血浆水平上升在健康人的血浆胰岛素水平上。我们对Cela2a功能的表征揭示了其能力触发胰岛素的分泌和灵敏度。相反，发现在队列增加了血小板聚集并降低胰岛素敏感性。从机械上讲，发现Cela2a 蛋白水解清除GPCR，例如PAR2并影响AMPK的PAR2依赖性激活，而突变体 CELA2AS触发不同的PAR2依赖性途径，导致ERK增加并减少AMPK 激活。那就是cela2a似乎是一种par2的内源配体，这是一种隐含的GPCR 葡萄糖稳态的调节。这些功能强调了Cela2a作为新型危险因素的作用，用于治疗T2D的有吸引力的治疗靶标。我们将研究 cela2a并探索其在全球，腺泡细胞和肠道特异性的Cela2a敲除小鼠，具有焦点PAR2依赖性途径。 cela2a ko小鼠是理想的选择当他们显示出胰岛素敏感性受损，肝炎和血浆甘油三酸酯的效果受损时的目标人类的表型。