Brain VDR Regulate Glucose Balance

Brain VDR 调节血糖平衡

基本信息

批准号：
10444524
负责人：
Stephanie Renee Sisley
金额：
$ 48.28万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-05 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444524
关键词：
Acute Affect Agonist American Animals Blood Glucose Body Weight Brain Calcitriol Caring Cells Clinical Trials Data Development Diabetes Mellitus Diet Disease Energy Intake Enterobacteria phage P1 Cre recombinase Equilibrium Fasting Future Genetic Genetic Models Genomics Glucose Glucose tolerance test Goals Grant High Fat Diet Hypertension Hypothalamic structure Immunohistochemistry Individual Inflammation Insulin Resistance Knowledge Ligands Literature Mediating Medical Methods Modeling Molecular Mus Neurons Non-Insulin-Dependent Diabetes Mellitus Obesity Other Genetics Peripheral Physiological Population Property Public Health Publishing Regulation Research Risk Rodent Role Techniques Testing Therapeutic Agents Therapeutic Clinical Trial Thinness Viral Vitamin D Vitamin D3 Receptor Weight Work blood glucose regulation diabetes mellitus therapy diabetes pathogenesis dietary dietary manipulation effective therapy euglycemia experimental study glucose production glucose tolerance impaired glucose tolerance improved innovation insight intraperitoneal mind control mouse model neural circuit neuronal circuitry new therapeutic target novel novel strategies prevent protective effect receptor expression receptor function response single-cell RNA sequencing stem tool transcriptomics

项目摘要

Our lack of understanding regarding how vitamin D regulates glucose prevents its use as an effective diabetes therapy. We have shown that vitamin D can act in the brain to lower glucose levels and that loss of vitamin D receptors (VDR) within the paraventricular hypothalamus (PVH) of the brain are critical for normal glucose levels in obese, but not lean, animals. However, the neurocircuitry/function of VDRPVH neurons, the role of the PVH VDR responding to dietary vitamin D, and mechanisms underlying effects in obese but not lean states are unknown. This raises basic questions regarding how vitamin D receptors mediate glucose balance. We have generated a genetic mouse model with Cre recombinase expression in VDR positive cells (VDRCre). This provides an excellent model to determine the function, necessity, and downstream neuronal targets of VDRPVH neurons. Additionally, utilizing other genetic tools, we can determine if VDR within the PVH are necessary for changes in blood glucose by dietary vitamin D. Last, we can utilize these tools to determine the mechanisms underlying weight-specific effects of vitamin D in the brain on glucose regulation. The objective of this grant is to determine the mechanisms of vitamin D in the brain on glucose balance. We hypothesize that VDR regulate glucose levels through distinct neuronal circuits and through genomic effects in PVH neurons. The central hypothesis will be tested by three specific aims: 1) identifying neuronal mechanisms for PVH VDR positive neurons; 2) determining if PVH VDR are required or sufficient for dietary-vitamin D changes in glucose homeostasis; and 3) establishing mechanisms for the glucose-protective effect of vitamin D in an obese model. In Aim 1, we will use chemogenetics, single-cell genomics, and immunohistochemistry to determine the function, identity, and circuitry of VDRPVH neurons. In Aim 2, we will use different dietary manipulations of vitamin D to test if PVH VDR are necessary for high-vitamin D induced glucose improvements. Additionally, we will determine if central administration of active vitamin D can overcome deleterious effects of low dietary vitamin D on glucose balance. In Aim 3, we will determine how obesity alters the transcriptomic and neuronal activation response to active vitamin D (1,25D3). Additionally, we will determine if there are differences in VDR expression or VDR+ neuronal number in obese vs. lean states. The research proposed is innovative, because it investigates the function of a novel neuronal population (VDRPVH) on glucose tolerance, using a novel mouse model. The proposed research is significant because it is expected to identify new paradigms to understand vitamin D action, as well as possibly identifying a novel circuit in the PVH with critical glucose-regulating properties. Results from this research may ultimately explain some of the variance in clinical trials utilizing vitamin D as a therapy and provide critical information to advance the use of vitamin D as a therapeutic agent. Altogether, I envision that the completion of this proposal will move this research towards the long-term goal of understanding how to utilize vitamin D as an effective therapy for type 2 diabetes.

我们对维生素 D 如何调节血糖缺乏了解，阻碍了其作为有效的糖尿病药物的应用治疗。我们已经证明，维生素 D 可以在大脑中发挥作用，降低血糖水平，并且维生素 D 的损失大脑室旁下丘脑 (PVH) 内的受体 (VDR) 对于正常血糖至关重要肥胖动物（而非瘦动物）中的水平。然而，VDRPVH 神经元的神经回路/功能、 PVH VDR 对膳食维生素 D 的反应，以及对肥胖而非瘦状态的潜在影响机制未知。这就提出了有关维生素 D 受体如何介导葡萄糖平衡的基本问题。我们有建立了在 VDR 阳性细胞 (VDRCre) 中表达 Cre 重组酶的遗传小鼠模型。这提供了一个优秀的模型来确定 VDRPVH 的功能、必要性和下游神经元靶点神经元。此外，利用其他遗传工具，我们可以确定 PVH 内的 VDR 是否对于膳食维生素 D 会改变血糖。最后，我们可以利用这些工具来确定其机制大脑中维生素 D 对血糖调节的潜在体重特异性影响。这笔赠款的目的是确定大脑中维生素 D 对葡萄糖平衡的机制。我们假设 VDR 调节通过不同的神经元回路和 PVH 神经元的基因组效应来调节葡萄糖水平。中央该假设将通过三个具体目标进行检验：1）确定 PVH VDR 阳性的神经元机制神经元； 2) 确定 PVH VDR 对于膳食维生素 D 葡萄糖变化是否是必需的或足够的体内平衡； 3) 建立维生素 D 在肥胖模型中的葡萄糖保护作用机制。在目标 1 中，我们将使用化学遗传学、单细胞基因组学和免疫组织化学来确定 VDRPVH 神经元的功能、身份和电路。在目标 2 中，我们将使用不同的饮食控制维生素 D 来测试 PVH VDR 是否是高维生素 D 诱导的血糖改善所必需的。此外，我们将确定集中施用活性维生素 D 是否可以克服低饮食的有害影响维生素 D 对葡萄糖平衡的影响。在目标 3 中，我们将确定肥胖如何改变转录组和神经元对活性维生素 D (1,25D3) 的激活反应。此外，我们将确定 VDR 是否存在差异肥胖与瘦状态下的表达或 VDR+ 神经元数量。所提出的研究具有创新性，因为它使用新型小鼠研究了新型神经元群 (VDRPVH) 对葡萄糖耐量的功能模型。拟议的研究意义重大，因为它有望找到新的范式来理解维生素 D 的作用，以及可能确定 PVH 中具有关键葡萄糖调节作用的新回路特性。这项研究的结果可能最终解释了临床试验中使用的一些差异维生素 D 作为一种疗法，并为推进维生素 D 作为治疗剂的使用提供重要信息。总而言之，我预计该提案的完成将推动这项研究朝着以下长期目标迈进：了解如何利用维生素 D 作为 2 型糖尿病的有效疗法。