Deconstructing insulin in the brain

解构大脑中的胰岛素

• 批准号: 10688804
• 负责人: Josephine Egan
• 金额: $ 27.91万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688804
• 关键词: 3xTg-AD mouse; APP-PS1; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid deposition; Animal Model; Area; Behavior; Blood Glucose; Brain; CB1 knockout; Calcium; Calcium Signaling; Calories; Cells; Cerebrum; Data Collection; Diabetes Mellitus; Diet; Endoplasmic Reticulum; Female; Gene Expression Profiling; Genes; Hormones; Human; Hyperglycemia; Hyperinsulinism; Hyperlipidemia; Hypoglycemia; In Situ Hybridization; Insulin; Insulin Receptor; Insulin Resistance; Lead; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Mus; Neurons; Ontology; Pancreas; Pathologic Processes; Pathway interactions; Peripheral; Phenotype; Proteins; Proteomics; Structure of choroid plexus; Testing; Tissue-Specific Gene Expression; Wild Type Mouse; experimental study; insulin secretion; insulin signaling; mouse model; novel; prevent; receptor

After initially carried out whole brain in situ hybridization for insulin in mouse, and we found that insulin expression (both mRNA and protein) in present in the Choroid Plexus (CP) of mice. Surprisingly, it was easily detectable in only CP, and no any other brain area. We also found lower insulin mRNA levels in the CP of young females in the 3XTg mice when compared to their age-matched control littermates (figure 1B). Differential gene expression analysis in their CP also substantiated this statement, as changes in gene ontology associated with the secretory and calcium signaling were confirmed. Therefore, we hypothesize that the CP secretory function, including insulin secretion, is altered in early stages of the Alzheimers disease pathological process. Our strategy now is to investigate calcium signaling in the CP (calcium signaling is required for insulin secretion) particularly the mobilization of intracellular calcium from the endoplasmic reticulum by IP3 receptors, as it likely is adversely affected in early ages of this animal model, and this in turn would alter the secretome in its entirety and not just insulin. We are also quantifying levels of other hormones known to be produced in the choroid plexus of APP/PS1 and wild type mice and we will carry out proteomics in order to build a secretory profile in the prodomal AD state. The exciting finding of abundant insulin in CP was unexpected and has opened a whole area of CP study, especially with aging and AD. So insulin is likely influencing insulin action from two sourcesCP-derived and pancreas-derived insulin.

我们首次对小鼠进行了全脑胰岛素原位杂交，发现小鼠脉络丛（CP）中存在胰岛素的表达（包括mRNA和蛋白）。令人惊讶的是，它只在CP中很容易检测到，而没有任何其他大脑区域。我们还发现，与其年龄匹配的对照同窝仔相比，3XTg小鼠中年轻雌性的CP中胰岛素mRNA水平较低（图1B）。在他们的CP中的差异基因表达分析也证实了这一说法，因为与分泌和钙信号传导相关的基因本体的变化得到了证实。因此，我们推测CP分泌功能，包括胰岛素分泌，在阿尔茨海默病的病理过程的早期阶段改变。我们现在的策略是研究CP中的钙信号传导（胰岛素分泌需要钙信号传导），特别是IP 3受体从内质网中动员细胞内钙，因为它可能在该动物模型的早期受到不利影响，这反过来会改变整个分泌组，而不仅仅是胰岛素。我们还对已知在APP/PS1和野生型小鼠脉络丛中产生的其他激素的水平进行定量，我们将进行蛋白质组学研究，以建立前体AD状态下的分泌谱。CP中丰富的胰岛素的令人兴奋的发现是出乎意料的，并且开辟了CP研究的整个领域，特别是与衰老和AD的关系。所以胰岛素可能从两个来源影响胰岛素的作用：CP来源的胰岛素和胰腺来源的胰岛素。