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

> **NIH NIH K01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2021 · $162,000

## Abstract

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-obesit...

## Key facts

- **NIH application ID:** 10281245
- **Project number:** 1K01HL155241-01A1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Paola Cecilia Rosas
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $162,000
- **Award type:** 1
- **Project period:** 2021-08-16 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10281245

## Citation

> US National Institutes of Health, RePORTER application 10281245, P21-activated kinase 1 is a novel regulator of cardiac and adipose tissue function in females (1K01HL155241-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10281245. Licensed CC0.

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