R01HL159764

Gonadal Hormones as Mediators of Sex and Gender Influences in Asthma - Abstract

Asthma is a lung disease caused by exaggerated lung inflammation, leading to airway obstruction and compromised airflow. Despite significant advances in its diagnosis and treatment, asthma continues to be a significant health problem affecting more than 25 million patients in the US and over 300 million around the world.

Well-characterized sex and gender differences in asthma have been reported, with changes in morbidity throughout life. Starting around puberty and peaking during mid-life, women have increased asthma prevalence and higher rates of asthma exacerbations than men. The causes of these disparities remain unclear; however, studies have shown that sex-specific inflammatory mechanisms controlled by hormones contribute to differences in airway reactivity in response to environmental stimuli.

Despite this, experimental models of asthma have not explored the contributions of sex hormones to inflammatory mechanisms in the female and male lung, and no studies have explored the effects of feminizing hormone therapy with estrogen in the lungs of trans women.

Prior studies from our laboratory using mouse models have reported sex differences and influences of the estrous cycle and circulating sex hormones in the inflammatory response to environmental exposures. Based on these findings, we hypothesized that female sex hormones, specifically estrogens, contribute to asthma phenotypes in the lung via activation of inflammatory mechanisms mediated by estrogen receptors.

In the proposed study, we will test this hypothesis by determining the mechanisms by which estrogen mediates sex and gender influences in asthma.

In Aim 1, we will determine the contributions of sex chromosome complement (XX vs. XY) vs. gonadal hormones in asthma phenotypes by developing a mouse house dust mite (HDM) asthma model on the Four Core Genotypes (FCG) model.

In Aim 2, we will study the contributions of estrogens to HDM-induced asthma outcomes using male and female gonadectomized mice treated with estradiol, as well as bronchial epithelial cells from male and female healthy and asthma patients exposed to HDM in the presence/absence of estrogen receptor agonists/antagonists.

In Aim 3, we will determine the roles of nuclear (ER) and membrane-bound (GPER-1) estrogen receptors in estrogen-mediated mechanisms of inflammation in HDM-induced asthma, using ER and GPER1 knockout mice.

Our studies will be the first to characterize estrogen-mediated mechanisms of inflammation in asthma phenotypes in the male and female lung, contributing to the characterization of sex- and gender-specific factors accounting for inter-individual differences, as well as the effects of feminizing hormone therapy in lung pathobiology.

We expect that our studies would serve to develop potential sex- and gender-specific treatments and recommendations for dosage of therapeutic agents to treat and prevent asthma in cis and transgender women.

Trustees Of Indiana University

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Bloomington, Indiana 47405 United States

Single Zip Code

Research Supplements to Promote Diversity in Health-Related Research (Admin Supp Clinical Trial Not Allowed) (PA-23-189)

Amendment Since initial award the total obligations have increased 533% from $497,030 to $3,148,325.