P21-activated kinase 1 is a novel regulator of cardiac and adipose tissue function in females

这里提出的实验提供了关键的培训和通往Paola Rosas博士的道路上的重要元素 职业目标侧重于理解性别、肥胖和心力衰竭之间的关系 保留射血分数(HFpEF，EF&GT；50%)。HFpEF更多见于绝经后妇女 (2：1)VS男性和肥胖患者。此外，女性的肥胖率和极端肥胖率高于男性。 然而，造成这些差异的原因尚不清楚。拟议的研究建立在以下初步证据的基础上 P21-激活蛋白激酶1(PAK1)在脂肪组织中的定位及其在女性脂肪积累中的作用 随着年龄的增长，这一点变得更加突出。老年雌性全局PAK1基因敲除(PAK1-/-)小鼠显著增加 内脏肥胖症，类似于绝经后女性。此外，随着年龄的增长，不同于雄性PAK1-/-小鼠， 雌性PAK1-/-小鼠表现出舒张期功能障碍。PAK1是一种多效性丝氨酸/苏氨酸蛋白激酶 证明对不同的应激源有心脏保护作用。在其他器官中，有证据表明，PAK1 参与雌激素信号通路；然而，这些过程尚未在心脏或心脏进行研究。 在脂肪组织中。这些发现导致了一种假设，即PAK1受到雌激素的调节，并且 由于缺乏雌激素，PAK1的调节失调，导致肥胖和HFpEF。随着这些发现在 请记住，我提出了以下目标。目的#1：探讨雌激素对脑内PAK1的调节机制 心脏和脂肪组织。我将研究心脏和脂肪中的雌激素是如何激活PAK1的 组织以及这种激活如何涉及雌激素受体α(ERα)和/或G蛋白偶联的雌激素受体 (GPER)。目的#2：探讨PAK1对雌性小鼠心脏功能的调节机制。这就做 研究PAK1基因敲除小鼠模型中PAK1缺失对细胞内钙离子的影响 肌丝的动力学和对钙离子的反应，从而影响心脏松弛。目标3：调查 PAK1调节雌性小鼠脂肪组织动态平衡的机制及其作用 心脏功能失调。我将研究脂肪组织中缺乏PAK1是如何促进 内脏肥胖症导致肥胖，进而影响女性心脏的舒张期功能。 影响：解决这些目标将极大地促进我们对PAK1在 通过探讨雌激素与脂肪组织功能的关系来调节女性心脏和脂肪组织的功能 心脏和脂肪组织中的PAK1信号。此外，这些贡献将解释，至少在 绝经后妇女HFpEF和肥胖的发生率较高。预计结果将带来 治疗HFpEF和女性肥胖症的新替代品和新视野。这项研究将 也为Rosas博士的第一个R01申请奠定了基础，以进一步研究PAK1作为 抗肥胖激酶和作为女性的代谢调节剂。

Experiments proposed here offer key training and significant elements in a path toward Dr. Paola Rosas’ career goals with focus on the understanding of the relations among gender, obesity and heart failure with preserved ejection fraction (HFpEF, EF>50%). HFpEF is more frequently seen in postmenopausal women (2:1) vs men and in obese patients. Moreover, obesity and extreme obesity are higher in women than men. However, the cause of these differences are unclear. Proposed studies build on preliminary evidence of localization of p21-activated kinase 1 (PAK1) in adipose tissue and its involvement in female fat accumulation that accentuates with aging. Aged female global PAK1 knock-out (PAK1-/-) mice exhibit significantly increased visceral adiposity, similar to post-menopausal women. Furthermore, with aging, unlike male PAK1-/- mice, female PAK1-/- mice show diastolic dysfunction. PAK1 is a pleiotropic serine/threonine protein kinase demonstrated to be cardio-protective against different stressors. There is evidence, in other organs, that PAK1 is involved in estrogen signaling pathways; however, these processes have not yet been studied in the heart or in the adipose tissue. These discoveries led to the hypothesis that PAK1 is regulated by estrogens, and that dysregulation of PAK1 due to lack of estrogens, contributes to obesity and HFpEF. With these findings in mind, I propose the following aims. Aim #1: Investigate the mechanisms by which estrogens regulate PAK1 in the heart and the adipose tissue. I will study how PAK1 is activated by estrogens in the heart and the adipose tissue and how this activation involves estrogen receptor α (ERα) and/or G protein-coupled estrogen receptor (GPER). Aim #2: Investigate the mechanisms by which PAK1 regulates cardiac function in female mice. I will study how the absence of PAK1 in a PAK1-cardiac specific knock-out mouse model, affects intracellular Ca2+ kinetics and the response of myofilaments to Ca2+, thereby affecting cardiac relaxation. Aim #3: Investigate the mechanisms by which PAK1 regulates adipose tissue homeostasis in female mice and the effect of its dysregulation on cardiac function. I will examine how lack of PAK1 in adipose tissue promotes increased visceral adiposity leading to obesity which subsequently affects diastolic function in the female heart. Impact: Addressing these aims will significantly advance our understanding of the role of PAK1 on the regulation of cardiac and adipose tissue function in females, by exploring the relation between estrogens and PAK1 signaling in the heart and the adipose tissue. Furthermore, these contributions will explain, at least in part, the higher incidence of HFpEF and obesity in post-menopausal women. Results are expected to bring novel alternatives and open new horizons in the treatment of HFpEF and obesity in women. This research will also form the basis for Dr. Rosas’ first R01 application to conduct further studies on the role of PAK1 as an anti-obesity kinase and as a metabolic regulator in women.