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

P21 激活激酶 1 是女性心脏和脂肪组织功能的新型调节剂

• 批准号: 10281245
• 负责人: Paola Cecilia Rosas
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10281245
• 关键词: Address; Adipose tissue; Affect; Aging; Area; Award; Biophysics; Brain; Brown Fat; Cardiac; Cardiac Myosins; Chicago; Data; EFRAC; Elements; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Exhibits; Failure; Family; Fatty acid glycerol esters; Fellowship; Female; Foundations; Functional disorder; Funding; Future; GPER gene; Gender; Goals; Grant; Heart; Heart Research; Heart failure; High Prevalence; Homeostasis; Hypertrophy; Illinois; Incidence; Kinetics; Knock-out; Knockout Mice; Learning; Menopause; Metabolic; Metabolism; Microfilaments; Mind; Modification; Morbid Obesity; Mus; Myocardial dysfunction; Obesity; Organ; Patients; Phosphorylation; Phosphotransferases; Physiology; Play; Postmenopause; Predisposing Factor; Premenopause; Process; Production; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Receptor Signaling; Regulation; Relaxation; Research; Resources; Role; Sex Ratio; Signal Pathway; Signal Transduction; Techniques; Testing; Training; Translating; Treatment Failure; Universities; Visceral; Woman; Work; age related; aged; cardioprotection; career; estrophilin; experimental study; heart function; heart preservation; high risk; male; member; men; mouse model; myosin-binding protein C; novel; obese patients; obesity treatment; older women; p21-activated kinase 1; preservation; response; skills; stressor

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.

这里提出的实验提供了关键的培训和重要的元素，以通向Paola Rosas博士的道路 职业目标专注于理解性别，肥胖和心力衰竭之间的关系 保留的射血分数（HFPEF，EF> 50％）。 HFPEF在绝经后妇女中更常见 （2：1）与男性和肥胖患者。此外，女性的肥胖和极端肥胖比男性高。 但是，这些差异的原因尚不清楚。拟议的研究以初步证据为基础 脂肪组织中p21激活的激酶1（PAK1）的定位及其参与雌性脂肪的积累 这会随着衰老而加重。老年女性全球PAK1淘汰赛（PAK1 - / - ）小鼠暴露显着增加 内脏肥胖，类似于绝经后妇女。此外，随着衰老的衰老，与雄性pak1 - / - 小鼠不同， 雌性PAK1 - / - 小鼠表现出舒张功能障碍。 PAK1是一种多效丝氨酸/苏氨酸蛋白激酶 证明对不同的压力源具有心脏保护。在其他器官中有证据表明Pak1 参与雌激素信号通路；但是，这些过程尚未在心脏中研究或 在脂肪组织中。这些发现导致了以下假设：Pak1受雌激素的调节，并且 由于缺乏雌激素，PAK1失调，导致肥胖和HFPEF。这些发现 介意，我提出以下目标。目的＃1：调查估计调节PAK1的机制 心脏和脂肪组织。我将研究如何在心脏和脂肪中被雌激素激活 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）。 AIM＃2：研究PAK1调节雌性心脏功能的机制。我会 研究PAK1-核心特异性敲除小鼠模型中PAK1的不存在，会影响细胞内Ca2+ 动力学和肌膜对Ca2+的反应，从而影响心脏放松。目标＃3：调查 PAK1调节雌性小鼠脂肪组织稳态及其作用的机制 心脏功能失调。我将检查脂肪组织中缺乏PAK1促进如何增加 内脏肥胖导致物体性，随后会影响女性心脏的舒张功能。 影响：解决这些目标将大大提高我们对PAK1在 通过探索雌激素与 PAK1信号在心脏和脂肪组织中。此外，这些贡献将至少在 一部分，在绝经后妇女中，HFPEF和肥胖症的较高事件。结果预计将带来 新颖的替代方案和开放的新视野，以治疗女性HFPEF和肥胖症。这项研究会 还构成了Rosas博士的第一个R01应用的基础，以进一步研究Pak1的作用 抗肥胖激酶和女性代谢调节剂。