Diabetic Memory in Hematopoietic Stem Cells

造血干细胞的糖尿病记忆

• 批准号: 10655742
• 负责人: Damien Reynaud
• 金额: $ 45.04万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655742
• 关键词: Adult; Adult Children; Adverse effects; Affect; Atherosclerosis; Automobile Driving; Biological Assay; Biological Markers; Cardiovascular Diseases; Cell Compartmentation; Cell Separation; DNA Methylation; Data; Development; Diabetes Mellitus; Diabetic mouse; Early Diagnosis; Epigenetic Process; Event; Exposure to; Generations; Genetic; Gestational Diabetes; Goals; Health; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Human; Human Pathology; Inflammation; Knowledge; Maintenance; Memory; Metabolic; Metabolic stress; Modeling; Modification; Molecular; Molecular Target; Morbidity - disease rate; Mothers; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity Epidemic; Pathologic; Pathology; Pathway interactions; Pattern; Perinatal; Phenotype; Population; Predisposition; Pregnancy; Pregnancy Complications; Prevalence; Receptor Signaling; Research; Risk; Role; Signal Transduction; Sterility; Testing; Therapeutic Intervention; Toll-like receptors; United States; Up-Regulation; Woman; Work; blood glucose regulation; clinically relevant; diabetic; improved; in utero hyperglycemia; long term memory; medical complication; methylome; mouse model; new therapeutic target; novel; novel diagnostics; novel therapeutics; offspring; pharmacologic; potential biomarker; prevent; prophylactic; receptor; receptor for advanced glycation endproducts; tool; transmission process

PROJECT DESCRIPTION One in six pregnancies is affected by some form of gestational diabetes (GD), a prevalence that is steadily rising in the context of the worldwide epidemics of obesity and early diabetic onset. Early diagnosis and advances in maternal glucose control have greatly mitigated the perinatal consequences of gestational diabetes on the mothers and their offspring. However, these advances have only marginally impacted its long-term consequences. As such, exposure to hyperglycemia in utero remains associated with increased long-term morbidities in offspring. The mechanisms driving this pathological transmission across generations have not been established. The overarching hypothesis of this project is that the hematopoietic stem cells (HSCs) of the offspring are stably altered by gestational diabetes and are essential “effectors” of the long-term pathological effects of gestational diabetes in offspring. Our preliminary data established two reliable mouse models of gestational diabetes that reproduce not only the perinatal adverse features of the human pathology, but also its long-term consequence in adult offspring. In these models, we show that gestational diabetes alters the hematopoiesis of the offspring and that this effect persists to adulthood, even in absence of overt diabetes. This phenotype indicates the acquisition of a long-lasting memory of metabolic events by the most upstream hematopoietic stem cell (HSC) compartments. Importantly, our results also indicate that hematopoietic alterations present in offspring can contribute to pathologies, such as atherosclerosis. Here we propose to investigate the interplay between gestational diabetes and the hematopoietic system. Based on our preliminary data, we will determine in aim 1 how signaling through the receptor of advanced glycation end products (RAGE) contributes to the acquisition of a diabetic hematopoietic memory in GD offspring. In aim 2, we will establish the epigenetic modifications that underlie the long-term maintenance of this hematopoietic memory in adult GD offspring. Our work will decipher the mechanisms underlying the hematopoietic memory associated with gestational diabetes. Defining these mechanisms will establish potential biomarkers for diabetic hematopoietic memory. it will also reveal new therapeutic targets to alter the trajectory of the hematopoietic memory and prevent its long-term pathological consequences.

项目描述 六分之一的怀孕受某种形式的妊娠糖尿病（GD）影响，这种流行率正在稳步上升 在肥胖和早期糖尿病发作的全球情节中。早期诊断和进步 孕产妇的葡萄糖控制大大减轻了妊娠糖尿病对围产期后果 母亲及其后代。但是，这些进步只影响了其长期 结果。因此，子宫内高血糖的暴露与长期增加有关 后代的病态。推动这种病理传播的机制尚未 建立了。该项目的总体假设是造血干细胞（HSC） 妊娠糖尿病稳定改变后代，是长期病理的必要“效应子” 妊娠糖尿病在后代的影响。我们的初步数据建立了两个可靠的鼠标模型 妊娠糖尿病不仅复制人类病理的围产期不良特征，而且再现 成人后代的长期后果。在这些模型中，我们表明妊娠糖尿病改变了 后代的造血症，即使没有明显的糖尿病，这种影响仍然存在于成年。这 表型表明在上游最持久的代谢事件的持久记忆 造血干细胞（HSC）室。重要的是，我们的结果还表明造血 后代中存在的改变会导致病理，例如动脉粥样硬化。在这里我们建议 研究妊娠糖尿病与造血系统之间的相互作用。基于我们的初步 数据，我们将在AIM 1中确定如何通过高级糖基化最终产品的接收器发出信号（RAGE） 有助于在GD后代获得糖尿病造血记忆。在AIM 2中，我们将确定 成人GD中这种造血记忆的长期维持的表观遗传修饰是基于长期维持的基础 后代。我们的工作将破坏与造血记忆相关的造血记忆的机制 妊娠糖尿病。定义这些机制将建立潜在的糖尿病造血生物标志物 记忆。它还将揭示新的治疗靶标，以改变造血记忆的轨迹并防止 它的长期病理后果。