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

这里提出的实验为保拉罗萨斯博士的“ 职业目标，重点是了解性别，肥胖和心力衰竭之间的关系， 射血分数保留（HFpEF，EF>50%）。HFpEF更常见于绝经后女性 （2：1）与男性和肥胖患者相比。此外，女性肥胖和极度肥胖的比例高于男性。 然而，这些差异的原因尚不清楚。拟议的研究基于以下初步证据： p21激活激酶1在脂肪组织中的定位及其与女性脂肪堆积的关系 随着年龄的增长而加重。老年雌性PAK 1全基因敲除（PAK 1-/-）小鼠表现出显著增加的 内脏肥胖，与绝经后妇女相似。此外，随着年龄的增长，与雄性PAK 1-/-小鼠不同， 雌性PAK 1-/-小鼠显示舒张功能障碍。PAK 1是一种多效丝氨酸/苏氨酸蛋白激酶 被证明对不同的压力源有心脏保护作用。有证据表明，在其他器官中，PAK 1 参与雌激素信号通路;然而，这些过程尚未在心脏或 在脂肪组织中。这些发现导致了PAK 1受雌激素调节的假设， 由于缺乏雌激素导致的PAK 1的失调，导致肥胖和HFpEF。随着这些发现在 在此，我提出以下目标。目的#1：研究雌激素调节PAK 1的机制， 心脏和脂肪组织我将研究PAK 1是如何被心脏和脂肪组织中的雌激素激活的。 组织以及这种激活如何涉及雌激素受体α（ERα）和/或G蛋白偶联雌激素受体 （GPER）。目的#2：研究PAK 1调节雌性小鼠心脏功能的机制。我会 研究PAK 1-心脏特异性敲除小鼠模型中PAK 1的缺失如何影响细胞内Ca 2 + 动力学和肌丝对Ca 2+的反应，从而影响心脏舒张。目标#3：调查 PAK 1调节雌性小鼠脂肪组织稳态的机制及其对脂肪组织稳态的影响 心脏功能失调。我将研究脂肪组织中PAK 1的缺乏如何促进增加 内脏肥胖导致肥胖，随后影响女性心脏的舒张功能。 影响：实现这些目标将大大促进我们对PAK 1在 调节女性心脏和脂肪组织功能，通过探索雌激素与 心脏和脂肪组织中的PAK 1信号。此外，这些贡献将解释，至少在 部分原因是绝经后妇女HFpEF和肥胖的发生率较高。预计结果将带来 新的替代方案，并在HFpEF和女性肥胖症的治疗中开辟了新的视野。这项研究将 这也是罗萨斯博士第一次申请R 01的基础，以进一步研究PAK 1作为一种 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.