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。高饱和脂肪的饮食是 与高血压的发展日益相关，尽管病理生理机制 对高血压的发展负有责任的人仍然知之甚少。这份提案考察的是一部小说 慢性高饱和脂肪饮食(HFD)激活免疫系统促进 肥胖和血压(BP)增加。此外，尽管年轻女性通常受到保护，不受 高血压相对于年龄匹配的男性来说，流行病学研究表明对心血管的保护 通常与年轻女性有关的是长期食用高饱和脂肪的饮食。 我们的研究将检验这一新的中心假设，即慢性HFD会导致 雌性通过特定性别的免疫细胞激活和招募。研究将进一步检验这一假设 女性中NLRP3的较大激活会导致慢性HFD患者免疫细胞活性增强。脂肪组织 是免疫细胞激活、高血压和NLRP3炎症小体之间的重要中介 会导致脂肪组织发炎。拟议的实验将扩大我们对HFD如何 通过测试两个特定的目标来促进成年男性和女性高血压的发展。目标1将 在女性慢性肾衰患者中，NLRP3的较大激活会导致更多的促炎作用，这一假设得到了验证 与男性相比，免疫细胞图谱导致更大的血压上升。实验将测量其影响 HFD对雄性和雌性大鼠NLRP3表达和激活的影响，评估NLRP3在HFD- 使用新的基因敲除诱导炎症和高血压的增加，并开始翻译我们的 检测黑白、瘦肉和黑种人分离的外周血单核细胞中NLRP3的结果 肥胖的男人和女人。目标2将验证免疫细胞促进较大脂肪组织的假设 患有HFD的女性的扩张性。实验将确定HFD对巨噬细胞和T细胞的影响 转录谱和脂肪组织具有性别特异性，评估NLRP3和T细胞在HFD- 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 组织移植评估T细胞与脂肪组织在高脂诱导的脂肪细胞中的相对贡献 扩张、炎症和高血压，以及确定性别是否影响BMI、 人类受试者队列中的BP、炎症和心血管疾病风险。针对青光眼病理生理原因的治疗 高血压无疑将提高血压控制率，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诱导高血压的免疫机制的理解 利用新的方法，揭示新的范例，并提供具有改进潜力的见解 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.