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.

这一补充申请旨在测试如何产妇低蛋白饮食暴露在胎儿发育 影响出生后小鼠下丘脑和海马神经元的功能和活力。的 假设子宫内因素调节胚胎神经元祖细胞的DNA甲基化; 这种甲基化模式预先决定了关键神经元基因的表达水平， 老年痴呆症和相关疾病（ADRD）的风险。具体而言，我们将重点关注 来源于表达转录因子Neurogenin 3（a.k.a. Neurog 3或Ngn 3）。已发表的研究表明，这些Ngn 3+祖细胞在大脑中产生神经元。 下丘脑和海马，其功能恶化与ADRD密切相关。因此，我们将 纯化小鼠脑中的胚胎Ngn 3+神经祖细胞及其成年后代， 检查这些细胞的甲基化组和转录组。这些模式将直接比较 对照小鼠和暴露于母体低蛋白饮食的小鼠。此外，免疫测定在一些关键的候选人 将进行基因，包括Syt 1，Syt 7，APP和Tau，对神经元功能和相关 与ADRD，分别。我们的初步数据显示，这两个候选人的调控DNA 甲基化证明了这些测定的合理性。还将使用基本的行为测定来将生理学上的 表型与DNA甲基化状态。值得注意的是，这些研究与将在 亲本R 01的目的3，其检查子宫内因素如何影响 Ngn 3+胰岛β细胞祖细胞及其成年后代在2型糖尿病（T2 D）背景下的功能。 因此，这些补充剂研究依赖于相同的小鼠模型、相同的技术和相似的专业知识 如R 01中所述。更重要的是，人们早就认识到T2 D和ADRD是 这两种疾病的发病率密切相关;这两种疾病的发病率都受到宫内病史的严重影响。因此，在本发明中， 研究Ngn 3+谱系的发育/功能中的重叠和不同机制，其中一个是 胰腺，另一个在大脑中，预计将产生潜在的目标，以干扰发展， 疾病