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

• 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
• 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

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进展为2型糖尿病（T2D）的分子机制不是 这可能揭示了减少T2D负担的治疗机会。我们最近发现 CELA 2A基因中的致病性功能丧失突变（Esteghamat & Mani，Nat. Genet. 2019），其中 编码胰弹性蛋白酶糜蛋白酶样弹性蛋白酶2A，具有极端的表型， 代谢综合征、2型糖尿病和早发性动脉粥样硬化。有趣的是， 相关研究也显示CELA2A基因中的常见变异与 血压，LDL胆固醇和BMI，强调其在一般人群疾病中的作用。 虽然只知道它作为胰腺外分泌酶的功能，但我们发现它是一种循环蛋白 表达于胰腺外组织包括肠道它的血浆水平在每餐后平行上升 健康人的血浆胰岛素水平。我们对CELA 2A功能的表征揭示了其在细胞内表达的能力。 触发胰岛素分泌和敏感性。相比之下，在大肠杆菌中发现的无催化活性的突变CELA2A蛋白质， 该队列增加了血小板聚集并降低了胰岛素敏感性。从机制上讲，发现CELA2A 蛋白水解切割GPCR如PAR 2并诱导PAR 2依赖性AMPK活化，而突变体 CELA2A触发不同的PAR 2依赖性途径，导致ERK增加和AMPK减少 activation.因此，CELA 2A似乎是PAR2的内源性配体，PAR2是一种GPCR，参与了 葡萄糖稳态的调节。这些功能强调了CELA2A作为新风险因素的作用， T2D治疗的一个有吸引力的治疗靶点。我们将研究的生理功能 CELA2A，并探讨其在全球，腺泡细胞葡萄糖稳态的分子机制， 肠道特异性Cela2a敲除小鼠，具有焦点PAR 2依赖性通路。Cela2a KO小鼠是理想的 这一目标，因为他们显示受损的胰岛素敏感性和增加的肝脏和血浆甘油三酯， 人类的表型