# Does sex matter? Targeting sex differences in age-related lung disease

> **NIH NIH R21** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $191,875

## Abstract

Currently, well-recognized, yet unexplained age and sex related differences in age-associated lung disease
may reflect actions of gonadal hormones and/or genes encoded on the sex chromosomes. The gap in
knowledge addressed in this proposal centers on whether this sex disparity is due to activational effects of
gonadal hormones (differential effects due to estrogen or testosterone) and/or sex chromosome complement.
This proposal has high impact since sex chromosome genes and/or sex hormones could potentiate protective
factors in females or harmful factors in males. This proposal is high risk as it goes beyond the simple idea that
gonadal hormones are the only players that make females different from males. We break down sex-biasing
factors into their component parts (e.g., hormones, sex chromosomes, and sex chromosome genes) and
manipulate each component while holding others constant to assess their contribution to the sex difference.
Preliminary data in this proposal show that in lung tissue obtained from male patients with idiopathic pulmonary
fibrosis (IPF), a fatal form of pulmonary fibrosis more common in middle aged and elderly men, there is a 30-
fold increase in androgen receptor (AR) mRNA accompanied by an increase in AR receptor protein. This data
strongly support the idea that activation by testosterone could promote downstream fibrotic pathways in an
age-associated lung disease like IPF. We hypothesize that a) aging male patients with IPF have more
severe lung disease due to androgen receptor-activated fibrotic pathways and b) sex differences in
lung fibrosis are caused in part by genes encoded by the sex chromosomes. Discovery of new
mechanisms to account for the sex disparity in age-associated lung fibrosis will uncover protective and/or
harmful factors that may lead to new diagnostic and therapeutic strategies. To detect sex-specific differential
pathways we will perform the following Aims:
Aim 1: Determine the activational effects of gonadal hormones/respective receptors and subsequent
downstream signaling that contribute to age-associated lung disease. A.These studies gonadectomize
(GDX) aging male and female BLM-treated mice to determine if estrogens are protective and androgens
harmful to lung fibrosis. B. Determine the contribution of AR and ER in the development of lung fibrosis using
myofibroblasts isolated from lungs of male and female patients with IPF.
Aim 2: Determine whether sex chromosomes contribute to sex differences in age-associated lung
disease using the four core genotypes (FCG) mouse model. This model separates the effects of gonadal
sex (ovaries versus testes) from the sex chromosome complement (XX vs. XY) by producing XX and XY
gonadal males and XX and XY gonadal females and will be done in collaboration with Dr. Arthur Arnold.

## Key facts

- **NIH application ID:** 9870855
- **Project number:** 5R21AG060338-02
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** SHARON J ELLIOT
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $191,875
- **Award type:** 5
- **Project period:** 2019-02-15 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870855

## Citation

> US National Institutes of Health, RePORTER application 9870855, Does sex matter? Targeting sex differences in age-related lung disease (5R21AG060338-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9870855. Licensed CC0.

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