Insulin Sensitivity In a Novel Mouse Model of ER Stress

新型 ER 应激小鼠模型中的胰岛素敏感性

• 批准号: 8461941
• 负责人: Matthew Clay Wheeler
• 金额: $ 14.85万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-04 至 2014-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461941
• 关键词: 2-tyrosine; Adipose tissue; Affect; Apoptosis; Binding Proteins; Biological Assay; Blood Glucose; Boxing; Caring; Cells; Chronic; Complex; Data; Development; Diabetes Mellitus; Diet; Disease; Endoplasmic Reticulum; Ethylnitrosourea; Euglycemic Clamping; Exhibits; Failure; Fasting; Fatty acid glycerol esters; Genes; Genetic Transcription; Gluconeogenesis; Glucose Clamp; Health; Hepatic; Hepatocyte; Human; Hyperglycemia; Incidence; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Lead; Liver; MAPK8 gene; Measures; Metabolic syndrome; Modeling; Mus; Muscle; Mutant Strains Mice; Mutation; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Occupations; PI3K/AKT; Pathway interactions; Pattern; Peripheral; Phosphorylation; Physiological; Physiological Processes; Play; Point Mutation; Prevention; Protein Import; Pyruvate; Rattus; Reporting; Research; Resistance development; Response Elements; Risk Factors; Role; Secondary to; Serine; Signal Transduction; Staging; Stress; Techniques; Testing; Therapeutic Intervention; Tissues; Tyrosine Phosphorylation; activating transcription factor; chromatin immunoprecipitation; endoplasmic reticulum stress; follow-up; in vivo; insulin receptor substrate 1 protein; insulin sensitivity; insulin signaling; member; mouse model; novel; promoter; therapeutic development; transcription factor

DESCRIPTION (provided by applicant): Type 2 diabetes is a disease marked by insulin resistance in peripheral tissues. One leading hypothesis to explain insulin resistance in the liver is the instigation of ER stress by high fat/western diet. We have recently characterized a mouse mutant that harbors an ENU induced point mutation in the Sec6111 gene that leads to diabetes via ER stress induced 2-cell apoptosis. By rescuing this mutation specifically in ¿ cells using a wild- type version of the gene driven by the rat insulin promoter, we uncovered ER stress in the liver that was a primary result of the mutation in Sec61a1. Since these mice have a normal ¿-cell compartment and normal levels of blood glucose, despite reduced circulating insulin levels we propose to use these mice to test three different hypotheses that will further clarify the role of ER stress in the development of hepatic insulin resistance. Our specific aims are: Specific Aim 1. Test the hypothesis that hepatic ER stress leads to insulin resistance and hepatosteatosis using a lean mouse model. Specific Aim 2. In a lean mouse model, test the hypotheses that (1) ER stress reduces hepatic insulin signaling and (2) that ER stress reduces gluconeogenesis. Specific Aim 3. Test the hypothesis that chronic ER stress influences the promoter occupation and transcription of metabolically relevant genes by the ER-stress-responsive transcription factor XBP1. This research can have immediate impact on the treatment of type 2 diabetes as a clearer view of the etiological circumstances that lead to insulin resistance can guide the development of therapeutic interventions and preventative care.

描述（由申请人提供）：2型糖尿病是一种以外周组织胰岛素抵抗为特征的疾病，解释肝脏胰岛素抵抗的一个主要假设是高脂肪/西方饮食引起的内质网应激。在 Sec6111 基因中含有 ENU 诱导的点突变，通过 ER 应激诱导 2 细胞凋亡来导致糖尿病。使用由大鼠胰岛素启动子驱动的基因的野生型版本的细胞，我们发现肝脏中的 ER 应激是 Sec61a1 突变的主要结果，因为这些小鼠具有正常的 ¿尽管循环胰岛素水平降低，但我们仍建议使用这些小鼠来测试三种不同的假设，以进一步阐明内质网应激在肝胰岛素抵抗发展中的作用。 1. 使用瘦小鼠模型检验肝脏 ER 应激导致胰岛素抵抗和肝脂肪变性的假设 2. 在瘦小鼠模型中，检验以下假设：(1) ER 应激会降低肝脏胰岛素信号传导，以及 (2)内质网应激减少糖异生。 测试慢性内质网应激影响内质网应激反应转录因子 XBP1 的启动子占据和转录的假设。这项研究可以对 2 型糖尿病的治疗产生直接影响。更清楚地了解导致胰岛素抵抗的病因情况可以指导治疗干预措施和预防性护理的发展。

项目成果

KDEL-retained antigen in B lymphocytes induces a proinflammatory response: a possible role for endoplasmic reticulum stress in adaptive T cell immunity.

B 淋巴细胞中保留的 KDEL 抗原诱导促炎反应：内质网应激在适应性 T 细胞免疫中的可能作用。

• DOI: 10.4049/jimmunol.181.1.256
• 发表时间: 2008
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Wheeler,MatthewC;Rizzi,Marta;Sasik,Roman;Almanza,Gonzalo;Hardiman,Gary;Zanetti,Maurizio
• 通讯作者: Zanetti,Maurizio