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 六分之一的孕妇受到某种形式的妊娠糖尿病（GD）的影响，患病率正在稳步上升 在肥胖症和早期糖尿病发病的世界范围内流行的背景下。早期诊断及进展 母亲的血糖控制大大减轻了妊娠期糖尿病对围产期的影响， 母亲和他们的孩子。然而，这些进展对其长期影响甚微。 后果因此，子宫内高血糖暴露仍然与长期高血糖增加相关。 后代的发病率驱动这种病理性代际传播的机制还没有 确立了习该项目的首要假设是， 妊娠期糖尿病会稳定地改变后代，并且是长期病理性糖尿病的重要“效应者”。 妊娠糖尿病对后代的影响我们的初步数据建立了两个可靠的小鼠模型， 妊娠期糖尿病不仅再现了人类病理学的围产期不良特征， 对成年后代的长期影响。在这些模型中，我们发现妊娠期糖尿病改变了 这种影响持续到成年期，即使没有明显的糖尿病。这 表型表明最上游获得了代谢事件的持久记忆 造血干细胞（HSC）区室。重要的是，我们的研究结果还表明， 后代中存在的改变可导致病理学，例如动脉粥样硬化。在此，我们建议 研究妊娠期糖尿病和造血系统之间的相互作用。根据我们初步的 数据，我们将在目标1中确定如何通过晚期糖基化终末产物（AGEs）受体的信号传导 有助于GD后代获得糖尿病造血记忆。在目标2中，我们将建立 表观遗传修饰是成人GD长期维持这种造血记忆的基础 后代我们的工作将破译造血记忆的机制， 妊娠糖尿病。明确这些机制将建立糖尿病造血的潜在生物标志物 记忆它还将揭示新的治疗靶点，以改变造血记忆的轨迹， 其长期的病理后果。