# The impact of sex and gender on disease progression, from developmental origins

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2024 · $423,609

## Abstract

Abstract
The maternal fetal interface is hormonal and immunologically rich environment that is important for normal 
placentation during the first trimester of pregnancy. This is also where adult diseases have developmental 
origins. Both the hormonal and immunologic milieus at this stage of gestation are already sexually dimorphic. 
We identified sexually dimorphic gene expression globally and among individual cell types of the first trimester 
placenta impacted by signaling at the maternal fetal interface, which includes members of the TGF-β superfamily, 
specifically TGFβ-1 and BMPs in males. Among individual cell types, ligands from the CCL family were most 
highly representative in females whereas IL1RN and MMP9 were highly expressed in males, with their 
corresponding receptors present on the maternal surface. Dihydrotestosterone, which is only produced by the 
male fetus, in addition to TGFβ1 and estradiol were identified as significant upstream regulators in individual cell 
types of the first trimester placenta. However, the hormonal environment may not be the only biologically sex 
different factor influencing the immune system, as we have also identified key transcription regulators in early 
gestation that may account for developmental origins of immune disease.
Throughout the lifespan, hormones have been implicated to play a significant role in immune dysfunction and 
development of disease, as overall there is a higher prevalence of autoimmune diseases in females, such as 
systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. Yet men are more likely to develop 
ankylosing spondylitis. Furthermore, males have increased prevalence of asthma compared to females in 
childhood, but the prevalence changes post-puberty, suggesting testosterone may be protective. 
Therefore, in order to better understand the influence of sex during developmental origins of immune function, 
including the effect of the hormonal milieu, we intend to identify sex specific transcriptional regulatory 
signatures in the first trimester placenta. Furthermore, since sex hormones are not dimorphic in early 
childhood, prior to puberty, we intend to better understand differences during development of the immune 
system at birth. Our goal is to identify sex unique regulators of immune dysfunction that can ultimately be 
used as a more personalized approach to treating immunologic diseases.

## Key facts

- **NIH application ID:** 10910890
- **Project number:** 5R01AI154535-05
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Margareta Pisarska
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $423,609
- **Award type:** 5
- **Project period:** 2020-09-10 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10910890

## Citation

> US National Institutes of Health, RePORTER application 10910890, The impact of sex and gender on disease progression, from developmental origins (5R01AI154535-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10910890. Licensed CC0.

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