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

从发育起源来看性别和性别对疾病进展的影响

• 批准号: 10260551
• 负责人: Margareta Pisarska
• 金额: $ 57.07万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10260551
• 关键词: Adult; Ankylosing spondylitis; Asthma; Autoimmune Diseases; Biological Process; Biological Response Modifiers; Cell physiology; Cells; Childhood; Chromatin; Cytokine Gene; Development; Disease; Disease Progression; Environment; Estradiol; Exposure to; Family; Female; Fetus; First Pregnancy Trimester; Flow Cytometry; Gender; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Gonadal Steroid Hormones; High Prevalence; Hormonal; Hormones; Immune; Immune System Diseases; Immune system; Immunity; Immunologics; Individual; Ligands; Longevity; MMP9 gene; Maternal-Fetal Exchange; Multiple Sclerosis; Peripheral Blood Mononuclear Cell; Placenta; Placentation; Play; Pregnancy; Prevalence; Puberty; Regulator Genes; Rheumatoid Arthritis; Role; Sex Differences; Signal Transduction; Stanolone; Surface; Systemic Lupus Erythematosus; Testosterone; Transcriptional Regulation; Transforming Growth Factor beta; XCL1 gene; anakinra; biological sex; cell type; cytokine; differential expression; early childhood; fetal; gender difference; hormone regulation; immune function; in utero; male; member; men; personalized approach; receptor; response; sex; sexual dimorphism; single-cell RNA sequencing; transcriptome

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 sexually dimorphic prevalence changes post-puberty, suggesting testosterone may be protective. There are also potential gender differences that influence the immune system. However, post puberty, hormonal regulation becomes sexually dimorphic again and it becomes difficult to separate the influence of hormones which is a function of biologic sex on the immune system from the influence of gender which is due to external influences. Therefore, in order to better understand the influence of biological 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 ar e not dimorphic in early childhood, prior to puberty, we intend to better understand the influence of gender on developmental differences of the immune system, prior to hormonal influences, to identify the critical drivers of sexual dimorphism in immune function. 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.

摘要