Mechanisms Driving Enhanced Susceptibility of Females versus Males to High-Fat Diet-Induced Increases in High Blood Pressure

女性与男性相比，对高脂肪饮食引起的高血压的易感性增强的机制

基本信息

批准号：
10714531
负责人：
Jennifer C Sullivan
金额：
$ 28.46万
依托单位：
AUGUSTA UNIVERSITY
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：
2023-09-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714531
关键词：
Address Adipocytes Adipose tissue Adoptive Transfer Adult Affect Age American Animal Experiments Automobile Driving Awareness Black race Blood Pressure Body Weight Body mass index Cardiovascular Diseases Cardiovascular system Cells Cessation of life Chronic Clinical Consumption Coronary heart disease Dahl Hypertensive Rats Data Development Diabetes Mellitus Diet Disease Dyslipidemias Environmental Risk Factor Epidemiology Fatty acid glycerol esters Female Gender Gene Expression Profile Genetic Genetic Models High Fat Diet Human Hypertension IL18 gene Immune Immune response Immune system In Vitro Inflammasome Inflammation Inflammatory Insulin Resistance Intake Interleukin-1 beta Kidney Knock-out Knowledge Link Macrophage Macrophage Activation Measures Mediating Metabolic Metabolism Molecular Nonesterified Fatty Acids Obesity Organ Predisposition Production Publishing Rattus Recommendation Risk Role Rural Sex Differences T-Cell Activation T-Lymphocyte Testing Therapeutic Thinness Tissue Expansion Tissue Transplantation Translating United States Vascular Diseases Woman Work blood pressure control blood pressure elevation cardiovascular disorder risk cardiovascular risk factor cohort cytokine epidemiology study experimental study high body mass index human subject immune activation improved in vivo insight kidney dysfunction male men metabolomics monocyte mortality novel novel strategies peripheral blood pharmacologic premature prevent recruit response saturated fat sensor sex targeted treatment young woman

项目摘要

Hypertension is world’s largest contributing factor to disease and mortality. Diets high in saturated fat are increasingly linked to the development of hypertension, although the patho-physiological mechanisms responsible for the development of hypertension remain poorly understood. This proposal examines a novel molecular mechanism by which a chronic high saturated fat diet (HFD) activates the immune system to promote increases in adiposity and blood pressure (BP). Moreover, although young women are typically protected from hypertension relative to age-matched men, epidemiological studies suggest that the cardiovascular protection typically associated with young women is compromised by chronic consumption of a diet high in saturated fat. Our study will examine the novel central hypothesis that a chronic HFD causes a greater increase in BP in females via sex-specific activation and recruitment of immune cells. Studies will further test the hypothesis that greater NLRP3 activation in females drives enhanced immune cell activation with a chronic HFD. Adipose tissue is a critical intermediary between immune cell activation and hypertension and the NLRP3 inflammasome contributes to adipose tissue inflammation. Proposed experiments will expand our understanding of how a HFD promotes the development of hypertension in adult males and females by testing two specific aims. Aim 1 will test the hypothesis that greater NLRP3 activation with chronic HFD in females results in a more pro-inflammatory immune cell profile compared to males resulting in greater increases in BP. Experiments will measure the impact of HFD on NLRP3 expression and activation in male and female rats, assess the contribution of NLRP3 to HFD- induced increases in inflammation and hypertension using novel genetic knockouts, and begin to translate our findings by measuring NLRP3 in isolated peripheral blood monocytes in a cohort of Black and White, lean and obese men and women. Aim 2 will test the hypothesis that immune cells promote greater adipose tissue expansion in females with a HFD. Experiments will determine if the impact of HFD on macrophage and T cell transcriptional profiles and adipose tissue is sex-specific, assess the contributions of NLRP3 and T cells to HFD- induced alterations in adipose tissue using novel genetic models, use adoptive transfer studies and adipose tissue transplants to assess the relative contributions of T cells vs. adipose tissue on HFD-induced adipocyte expansion, inflammation and hypertension, and determining if gender impacts the relationships between BMI, BP, inflammation and CVD risk in a human subject cohort. Therapies targeting the pathophysiological cause of hypertension will undoubtedly improve BP control rates and prevent premature death from CVD in both sexes. Results of this work will transform our understanding of immune mechanisms in HFD-induced hypertension by utilizing novel approaches, revealing new paradigms, and providing insight with the potential to improve clinical/therapeutic approaches for the treatment of disease.

高血压是世界上疾病和死亡率的最大因素。高饱和脂肪的饮食是尽管病理生理机制负责高血压的发展仍然知之甚少。该提案考试是一本小说慢性高饱和脂肪饮食（HFD）激活免疫系统以促进的分子机制肥胖和血压（BP）的增加。而且，尽管通常保护年轻女性免受高血压相对于年龄匹配的男性，流行病学研究表明心血管保护通常，与年轻女性相关的饱和脂肪的饮食长期消费会损害。我们的研究将研究新的中心假设，即慢性HFD会导致BP的更大增加通过性别特异性激活和免疫细胞募集的女性。研究将进一步检验以下假设女性中较大的NLRP3激活驱动慢性HFD增强了免疫球的激活。脂肪组织是免疫细胞激活和高血压与NLRP3炎症体之间的关键中介有助于脂肪组织注射。拟议的实验将扩大我们对HFD的理解通过测试两个特定目标，促进成年男性和女性的高血压发展。目标1意志检验以下假设，即女性中使用慢性HFD激活更大的NLRP3会导致促炎性促进性与雄性相比，免疫细胞的剖面导致BP增加。实验将测量影响 HFD在NLRP3表达和雄性大鼠中的激活中，评估NLRP3对HFD-的贡献使用新的遗传敲除诱导炎症和高血压增加，并开始翻译我们通过在孤立的外周血单核细胞中测量NLRP3的发现，黑白，瘦和肥胖的男人和女人。 AIM 2将测试免疫细胞促进更大脂肪组织的假设患有HFD的女性扩张。实验将确定HFD对巨噬细胞和T细胞的影响是否转录特征和脂肪组织是性别特异性的，评估NLRP3和T细胞对HFD-的贡献使用新型遗传模型，使用自适应转移研究和脂肪在脂肪组织中诱导改变组织移植以评估T细胞与脂肪组织对HFD诱导的脂肪细胞的相对贡献扩展，感染和高血压，并确定性别是否影响BMI之间的关系人类受试者队列中的BP，炎症和CVD风险。针对病理生理原因的疗法高血压无疑将提高BP的控制率，并防止两性中CVD过早死亡。这项工作的结果将改变我们对HFD诱导的高血压中免疫力学的理解使用新颖的方法，揭示新的范式并提供洞察力，并有可能改善疾病治疗的临床/治疗方法。