Time Restricted Feeding in Diet Induced Obesity Improves Aortic Damage and Endothelial Function Through Reducing Th17 Cells

饮食中的限时喂养通过减少 Th17 细胞改善主动脉损伤和内皮功能

基本信息

批准号：
10606103
负责人：
Claudia Edell
金额：
$ 4.77万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606103
关键词：
Acetylcholine Adaptive Immune System Affect Anti-Inflammatory Agents Antibodies Aorta Apolipoprotein E Autoimmunity Blood Vessels Butyrates CD4 Positive T Lymphocytes Cardiovascular Diseases Cardiovascular system Cause of Death Cells Chronic Darkness Data Diet Dietary Assessment Disodium Salt Nitroprusside Eating Endothelium Fasting Fatty acid glycerol esters Fellowship Fibrosis Flow Cytometry Food Functional disorder Future Goals Health High Fat Diet Histologic Histology Hour Hypertension Immune Immune system Immunoglobulin G Immunology Immunophenotyping Indirect Calorimetry Inflammation Inflammatory Intake Interleukins Intervention Knockout Mice Lesion Light Magnetic Resonance Measurement Measures Mediating Metabolic Metabolic dysfunction Modeling Mus Obesity Organ PTPRC gene Pathogenesis Pathogenicity Pathway interactions Physiologic pulse Physiology Plasma Population Production Propionates Protocols documentation Reducing diet Regulation Regulatory T-Lymphocyte Research Research Personnel Risk Factors Role Scientist T-Lymphocyte T-Lymphocyte Subsets Testing Th1 Cells Thick Thinness Time Time-restricted feeding Tissues United States Vasodilation Volatile Fatty Acids Weight Work cardiovascular disorder risk cardiovascular health cardiovascular risk factor career cytokine diet-induced obesity dietary endothelial dysfunction experimental study feeding graduate school high risk improved interleukin-23 microbial mouse model pre-doctoral receptor response single-cell RNA sequencing skills symposium tool development transcriptome sequencing transcriptomics

Acetylcholine Adaptive Immune System Affect Anti-Inflammatory Agents Antibodies Aorta Apolipoprotein E Autoimmunity Blood Vessels Butyrates CD4 Positive T Lymphocytes Cardiovascular Diseases Cardiovascular system Cause of Death Cells Chronic Darkness Data Diet Dietary Assessment Disodium Salt Nitroprusside Eating Endothelium Fasting Fatty acid glycerol esters Fellowship Fibrosis Flow Cytometry Food Functional disorder Future Goals Health High Fat Diet Histologic Histology Hour Hypertension Immune Immune system Immunoglobulin G Immunology Immunophenotyping Indirect Calorimetry Inflammation Inflammatory Intake Interleukins Intervention Knockout Mice Lesion Light Magnetic Resonance Measurement Measures Mediating Metabolic Metabolic dysfunction Modeling Mus Obesity Organ PTPRC gene Pathogenesis Pathogenicity Pathway interactions Physiologic pulse Physiology Plasma Population Production Propionates Protocols documentation Reducing diet Regulation Regulatory T-Lymphocyte Research Research Personnel Risk Factors Role Scientist T-Lymphocyte T-Lymphocyte Subsets Testing Th1 Cells Thick Thinness Time Time-restricted feeding Tissues United States Vasodilation Volatile Fatty Acids Weight Work cardiovascular disorder risk cardiovascular health cardiovascular risk factor career cytokine diet-induced obesity dietary endothelial dysfunction experimental study feeding graduate school high risk improved interleukin-23 microbial mouse model pre-doctoral receptor response single-cell RNA sequencing skills symposium tool development transcriptome sequencing transcriptomics

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项目摘要

PROJECT SUMMARY Cardiovascular disease (CVD) is the leading cause of death in the United States, and obesity is one of the highest risk factors for CVD. Our lab has shown that restricting intake of high fat diet (HFD) to the 12-hour active period for the last 2 weeks in a 20-week diet induced obesity (DIO) model significantly reduces aortic wall thickness and fibrosis and restores aortic endothelial function. We also found that DIO significantly increases aortic Th17 cells, which are an inflammatory CD4+ T cell subset that are known to drive progression of autoimmunity and organ damage. Interestingly, time restricted feeding (TRF) in the final 2 weeks of the DIO protocol reduced aortic Th17 cells. Th17 cells are the main producer of the inflammatory cytokine, IL-17A. IL- 17A has been known to drive CVD risk factors, however, it is unclear if TRF reduces aortic damage via the IL- 17A pathway. Furthermore, we have preliminary data that TRF in DIO is associated with greater circulating propionate and butyrate, which are two important microbial-derived short chain fatty acids (SCFA). SCFA are important for regulating hypertension and promoting anti-inflammatory T cell subsets, however, their role in DIO induced tissue damage is unclear. DIO is associated with decreased SCFA production, which could indicate that propionate and butyrate are necessary for protection against DIO damage. This led us to hypothesize that reduction of IL-17A and increased SCFA with TRF drive aortic protection and improved endothelial function in DIO. We will use C57Bl6/J mice for our 20-week DIO model with TRF intervention in the final two weeks of feeding. During those 2 weeks, mice will receive anti-mouse IL-17A or IgG antibody daily at Zeitgeber Time (ZT) 0, the start of the inactive period. Using these groups, we will assess aortic damage via pulse wave velocity (PWV) and histology. We will also assess endothelial function via vascular reactivity by stimulating the aorta with acetylcholine to assess endothelial dependent vasorelaxation. Sodium nitroprusside is used to assess endothelial independent vasorelaxation. Furthermore, we will use our TRF intervention in DIO to assess pathogenicity of Th17 cells in the aorta via single cell RNA sequencing. Th17 cells that upregulate the IL-23 receptor (IL-23R) are known to have greater pathogenic capabilities. In aim 2, we will use our 20-week DIO model with C57Bl6/J mice. During the final two weeks, the diet will be supplemented with 5% butyrate and propionate by weight in the inactive period as that is where we see increase of circulating SCFA. We will assess how dietary SCFA affects aortic Th17 cells via flow cytometry. Flow cytometry will allow us to immunophenotype the cells to identify if SCFA have an effect specifically on Th17 cells. We will also assess aortic damage and function via histology and PWV measurements at the conclusion of the 20-week DIO protocol. Endothelial function will also be assessed via vascular reactivity experiments. The main goal of this proposal is to identify how TRF in DIO improves aortic damage and endothelial function through regulation of Th17 cell pathogenicity.

项目摘要心血管疾病（CVD）是美国死亡的主要原因，肥胖是其中之一 CVD的最高风险因素。我们的实验室表明，将高脂饮食（HFD）限制为12小时的活动在20周饮食诱发肥胖症（DIO）模型的最后2周内的周期大大降低了主动脉壁厚度和纤维化并恢复主动脉内皮功能。我们还发现DIO显着增加主动脉Th17细胞，它是炎症性CD4+ T细胞子集，已知可以驱动的进展自身免疫性和器官损坏。有趣的是，在DIO的最后2周内，时间限制了进食（TRF）协议降低了主动脉Th17细胞。 Th17细胞是炎性细胞因子IL-17A的主要生产国。 il- 众所周知，17a驱动CVD危险因素，但是，尚不清楚TRF是否通过IL-降低主动脉损伤 17A路径。此外，我们有初步数据，即DIO中的TRF与更大的循环有关丙酸和丁酸酯是两个重要的微生物衍生的短链脂肪酸（SCFA）。 SCFA是但是，对于调节高血压和促进抗炎T细胞亚群至关重要，它们在DIO中的作用诱导的组织损伤尚不清楚。 DIO与SCFA生产降低有关，这可能表明丙酸和丁酸酯对于防止DIO损坏是必要的。这使我们假设通过TRF驱动主动脉保护减少IL-17A并增加SCFA，并改善了内皮功能 dio。在最后两周的最后两周中进食。在这两个星期中，小鼠将在Zeitgeber时间（ZT）每天接受抗小鼠IL-17A或IgG抗体 0，不活动时期的开始。使用这些组，我们将通过脉冲波速度评估主动脉损伤（PWV）和组织学。我们还将通过使用血管反应性来评估内皮功能乙酰胆碱以评估内皮依赖性血管延缓。亚硝普钠用于评估内皮独立的血管征。此外，我们将利用DIO中的TRF干预来评估主动脉中Th17细胞通过单细胞RNA测序的致病性。上调IL-23的Th17细胞已知受体（IL-23R）具有更大的致病能力。在AIM 2中，我们将使用20周的DIO 使用C57BL6/J小鼠的型号。在最后两个星期，饮食将补充5％丁酸酯和在不活跃的时期内，重量丙酸是我们看到循环SCFA增加的地方。我们将评估饮食SCFA如何通过流式细胞仪影响主动脉Th17细胞。流式细胞仪将使我们能够免疫表型细胞以识别SCFA是否对Th17细胞有特殊作用。我们还将评估主动脉损伤和在20周DIO方案结束时通过组织学和PWV测量功能。内皮功能还将通过血管反应性实验评估。该提议的主要目标是确定 DIO中的TRF如何通过调节Th17细胞致病性来改善主动脉损伤和内皮功能。