Using the KINGS diabetic mouse model to investigate sex differences underlying pancreatic islet biology and its dysfunction

使用 KINGS 糖尿病小鼠模型研究胰岛生物学及其功能障碍背后的性别差异

• 批准号: 2059725
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2059725
• 关键词: Using; KINGS; diabetic; mouse; model

Evidence for sexual dimorphisms in incidence, severity and pathophysiology of disease has accumulated in the lastdecade. A metabolic disease showing strong sex differences is diabetes mellitus, which is characterised by chronichyperglycaemia resulting from loss of glucose homeostasis.Understanding why sex differences exist in diabetes is important in the context of treatment; males and females mayrespond differently to existing therapies and studying sex differences may highlight factors that can be targeted for noveltherapies. Despite this, research in this area is lacking. An ER-stress-induced murine model of diabetes (the KINGSmouse) has recently been discovered at Kings College London. This model exhibits strong sexual dimorphisms indiabetic phenotype; whilst males develop overt diabetes at 5-weeks, females remain normoglycemic throughout theirlives despite having impaired glucose tolerance.To investigate what factors drive sex differences in the KINGS mouse, whether diabetes can be induced in femaleKINGS mice or alleviated in male KINGS mice, and to investigate whether sex differences in this model can beapplied to human islets.In the first year of the project we will investigate sex differences in acute and chronic responses of B-cells to ER-stress.Acute responses will be investigated by developing an ex vivo islet assay where functional adaptation and resistance(acute responses) to ER-stress are measured. Chronic responses (proliferation, hypertrophy) will be analysed in vivothrough histology and molecular techniques. The second aim of the project will focus around modulating the in vivoenvironment to establish whether diabetes can be induced in female KINGS mice or alleviated in males since this willgive insight into in vivo factors that may drive sex differences. Finally, results from the KINGS mice will becompared to human islets to establish whether any similarities exist and determine whether the KINGS mouserepresents a suitable mode for studying diabetic sexual dimorphisms in humans.

在过去的十年中，关于性二态性在疾病的发病率、严重程度和病理生理学方面的证据不断积累。糖尿病是一种表现出强烈性别差异的代谢疾病，其特征是葡萄糖稳态丧失导致的慢性高血糖症。了解为什么糖尿病存在性别差异在治疗方面很重要;男性和女性对现有疗法的反应可能不同，研究性别差异可能会突出新疗法的靶向因素。尽管如此，这方面的研究仍然缺乏。伦敦国王学院最近发现了ER应激诱导的糖尿病小鼠模型（KINGSmouse）。该模型在糖尿病表型中表现出强烈的性二态性;虽然雄性在5周时发展为明显的糖尿病，但雌性在其一生中保持血糖正常，尽管具有受损的葡萄糖耐量。为了研究是什么因素驱动KINGS小鼠中的性别差异，糖尿病是否可以在雌性KINGS小鼠中诱导或在雄性KINGS小鼠中减轻，并研究该模型中的性别差异是否可以应用于人类胰岛。在项目的第一年，我们将研究B细胞对ER的急性和慢性反应的性别差异。将通过开发离体胰岛测定来研究急性反应，其中测量对ER-应激的功能适应和抗性（急性反应）。将通过组织学和分子技术在体内分析慢性反应（增殖、肥大）。该项目的第二个目标将集中在调节体内环境，以确定糖尿病是否可以在雌性KINGS小鼠中诱导或在雄性中缓解，因为这将深入了解可能导致性别差异的体内因素。最后，KINGS小鼠的结果将与人类胰岛进行比较，以确定是否存在任何相似之处，并确定KINGS小鼠是否代表了研究人类糖尿病性二态性的合适模式。