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

高血压是世界上导致疾病和死亡的最大因素。高饱和脂肪的饮食 越来越多地与高血压的发展有关，尽管病理生理机制 导致高血压发展的原因仍然知之甚少。这份提案审查了一部小说 慢性高饱和脂肪饮食（HFD）激活免疫系统以促进 肥胖和血压（BP）增加。此外，虽然年轻女性通常受到保护， 高血压相对于年龄匹配的男性，流行病学研究表明， 通常与年轻女性相关的是由于长期食用高饱和脂肪的饮食而受到损害。 我们的研究将检验一个新的中心假设，即慢性HFD导致血压更大的增加， 雌性通过性别特异性激活和免疫细胞的募集。研究将进一步检验这一假设， 女性中更大的NLRP 3活化驱动慢性HFD的增强的免疫细胞活化。脂肪组织 是免疫细胞活化与高血压和NLRP 3炎性体之间的关键中介 导致脂肪组织炎症拟议的实验将扩大我们的理解，如何HFD 通过测试两个特定目标，促进成年男性和女性高血压的发展。目标1将 检验女性慢性HFD患者NLRP 3激活程度越高， 与男性相比，免疫细胞谱导致BP增加更大。实验将测量 HFD对雄性和雌性大鼠中NLRP 3表达和活化的影响，评估NLRP 3对HFD的贡献。 使用新的基因敲除诱导炎症和高血压的增加，并开始将我们的 通过测量黑人和白色人、瘦型人和非瘦型人的队列中分离的外周血单核细胞中的NLRP 3， 肥胖的男女目标2将检验免疫细胞促进更大脂肪组织的假设 在患有HFD的女性中扩张。实验将确定HFD对巨噬细胞和T细胞的影响 转录谱和脂肪组织是性别特异性的，评估NLRP 3和T细胞对HFD的贡献。 使用新的遗传模型诱导脂肪组织的改变，使用过继转移研究和脂肪 组织移植以评估T细胞相对于脂肪组织对HFD诱导的脂肪细胞的相对贡献 膨胀，炎症和高血压，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。针对疾病病理生理原因的治疗 高血压无疑会提高血压控制率，防止男女因心血管疾病而过早死亡。 这项工作的结果将改变我们对HFD诱导的高血压的免疫机制的理解， 利用新的方法，揭示新的范式，并提供具有改进潜力的洞察力 用于治疗疾病的临床/治疗方法。

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.