The DNA methylome-based regulation of functional beta-cell mass

基于 DNA 甲基化组的功能性 β 细胞群调节

• 批准号: 10287569
• 负责人: Guoqiang Gu
• 金额: $ 39.61万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10287569
• 关键词: Adult; Affect; Age; Age-Months; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Attenuated; B cell differentiation; B-Lymphocyte Subsets; Behavioral Assay; Beta Cell; Biological Assay; Brain; Brain region; Candidate Disease Gene; Cell Survival; Cell physiology; Cells; Cessation of life; DNA; DNA Methylation; DNA Modification Methylases; DNMT3a; Data; Deterioration; Development; Disease; Embryo; Endocrine; Enhancers; Epigenetic Process; Exposure to; Fetal Development; Foundations; Functional disorder; Genes; Goals; Haplotypes; Health; Hippocampus (Brain); Human; Hypothalamic structure; Immunoassay; Immunocompromised Host; Impairment; Instruction; Islet Cell; Islets of Langerhans; Learning; Link; Memory; Metabolic stress; Methylation; Modeling; Molecular; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Parents; Pattern; Phenotype; Physiological; Production; Protein-Restricted Diet; Publishing; Recording of previous events; Regulation; Risk; Sentinel; Techniques; Testing; Tissues; allotransplant; base; brain cell; diabetic; dosage; fitness; fitness test; gene function; genome-wide; improved; islet; islet stem cells; methylation pattern; methylome; mouse Neurog3 protein; mouse model; nerve stem cell; offspring; postnatal; progenitor; programs; response; stem cells; synaptotagmin VII; tau Proteins; transcription factor; transcriptome

This supplement application aims to test how maternal low-protein diet exposure during fetal development impacts the function and viability of neurons in postnatal mouse hypothalamus and hippocampus. The hypothesis is that intrauterine factors modulate the DNA methylomes of embryonic neuronal progenitor cells; this methylation pattern predetermines the expression levels of key neuronal genes and therefore preset the risk of Alzheimer’s diseases and related diseases (ADRD) in adult ages. Specifically, we will focus on the neurons that are derived from embryonic progenitor cells that express transcription factor Neurogenin 3 (a.k.a. Neurog3 or Ngn3). Published studies have shown that these Ngn3+ progenitors give rise to neurons in the hypothalamus and hippocampus, whose deteriorating function is closely associated with ADRD. Thus, we will purify embryonic Ngn3+ neural progenitor cells as well as their adult descendants in mouse brains and examine the methylome and transcriptome of these cells. These patterns will be directly compared between control mice and those exposed to maternal low-protein diet. In addition, immunoassays in some key candidate genes will be conducted, including Syt1, Syt7, APP, and Tau, important for neuronal function and associated with ADRD, respectively. Our preliminary data showing the regulation of these two candidates by DNA methylation justify these assays. Basic behavioral assays will also used to correlate the physiological phenotype with the DNA methylation states. Notably, these studies are parallel to what will be pursued in the Aim 3 of the parent R01, which examines how intrauterine factors impact the methylomes/transcriptomes of Ngn3+ islet beta-cell progenitors and the function of their adult progeny in the context of type 2 diabetes (T2D). These supplement studies therefore rely on identical mouse models, same techniques, and similar expertise as those proposed in the parent R01. More importantly, it has long been recognized that T2D and ADRD are tightly linked with each other; the risks of both diseases are heavily affected by the intrauterine history. Thus, examining the overlapping and distinct mechanisms in the development/function of Ngn3+ lineages, one in the pancreas the other in the brain, is expected to yield potential targets to interfere with the development both diseases.

这种补充剂的应用旨在测试胎儿发育过程中产妇低蛋白饮食的暴露方式 影响神经元在产后小鼠下丘脑和海马的功能和生存力。 假设是，插入因子调节胚胎神经祖细胞的DNA甲基甲基属。 这种甲基化模式预先确定关键神经元基因的表达水平，因此预设 成年时代的阿尔茨海默氏症疾病和相关疾病（ADRD）的风险。具体来说，我们将专注于 来自表达转录因子神经蛋白蛋白3的胚胎祖细胞的神经元（又称 Neurog3或ngn3）。已发表的研究表明，这些NGN3+祖细胞在 下丘脑和海马，其恶化与ADRD密切相关。那我们会的 纯化胚胎NGN3+神经祖细胞及其在小鼠大脑中的成年后代 检查这些细胞的甲基甲基和转录组。这些模式将直接比较 控制小鼠和暴露于母体低蛋白饮食的小鼠。此外，在一些关键候选人中进行免疫测定 将进行基因，包括SYT1，SYT7，APP和TAU，对神经元功能和相关 分别与Adrd。我们的初步数据显示了通过DNA对这两个候选者的调节 甲基化证明这些测定法。基本的行为分析也将用于关联生理 具有DNA甲基化状态的表型。值得注意的是，这些研究与将在 母体R01的AIM 3，它研究了内部因素如何影响甲基组/转录组 NGN3+胰岛β细胞祖细胞及其成人后代的功能在2型糖尿病（T2D）的背景下。 因此，这些补充研究依赖于相同的鼠标模型，相同的技术和相似的专业知识 正如父母R01中提出的那些。更重要的是，长期以来一直认识到T2D和ADRD是 彼此紧密相连；两种疾病的风险都受到内在病史的严重影响。那， 检查NGN3+谱系的开发/功能中的重叠和不同机制，其中一个 胰腺中的另一个在大脑中，有望产生潜在的目标来干扰发展 疾病。