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

基本信息

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
项目类别：
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

项目摘要

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.

这里提出的实验为保拉·罗萨斯博士的道路提供了关键的培训和重要的要素职业目标，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%）更常见于绝经后女性。 (2:1) 与男性以及肥胖患者相比，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。拟议的研究建立在初步证据的基础上。 p21 激活激酶 1 (PAK1) 在脂肪组织中的定位及其与女性脂肪积累的关系随着年龄的增长，老年雌性全 PAK1 敲除 (PAK1-/-) 小鼠表现出显着增加。内脏肥胖，与绝经后女性相似，此外，与雄性 PAK1-/- 小鼠不同，随着年龄的增长，雌性 PAK1-/- 小鼠表现出舒张功能障碍。 PAK1 是一种多效性丝氨酸/苏氨酸蛋白激酶。有证据表明，在其他器官中，PAK1 参与雌激素信号通路；然而，这些过程尚未在心脏或这些发现导致了 PAK1 受雌激素调节的假设。由于缺乏雌激素而导致的 PAK1 失调会导致肥胖和 HFpEF。请注意，我提出以下目标：研究雌激素调节 PAK1 的机制。心脏和脂肪组织我将研究心脏和脂肪中的雌激素如何激活 PAK1。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) 目标#2：研究 PAK1 调节雌性小鼠心脏功能的机制。研究 PAK1 心脏特异性敲除小鼠模型中 PAK1 的缺失如何影响细胞内 Ca2+ 动力学和肌丝对 Ca2+ 的反应，从而影响心脏舒张。目标 3：研究 PAK1调节雌性小鼠脂肪组织稳态的机制及其作用我将研究脂肪组织中 PAK1 的缺乏如何促进心脏功能的增加。内脏肥胖导致肥胖，进而影响女性心脏的舒张功能。影响：实现这些目标将显着增进我们对 PAK1 在通过探索雌激素与雌激素之间的关系来调节女性心脏和脂肪组织功能此外，这些贡献至少可以解释心脏和脂肪组织中的 PAK1 信号传导。部分，绝经后女性HFpEF和肥胖的发生率较高，预计将带来结果。这项研究将为女性 HFpEF 和肥胖症的治疗提供新的替代方案并开辟新视野。也为 Rosas 博士的第一个 R01 申请奠定了基础，以进一步研究 PAK1 作为抗肥胖激酶并作为女性的代谢调节剂。