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.

抽象的 母胎界面是一个荷尔蒙和免疫丰富的环境，对于正常的发育非常重要。 妊娠前三个月的胎盘植入。这也是成人疾病发展的地方 起源。在妊娠的这个阶段，激素和免疫环境都已经是两性二态的。 我们在全球范围内以及妊娠早期的各个细胞类型中发现了性二态性基因表达 胎盘受到母胎界面信号的影响，其中包括 TGF-β 超家族的成员， 特别是男性中的 TGFβ-1 和 BMP。在各个细胞类型中，来自 CCL 家族的配体最多 IL1RN 和 MMP9 在女性中高度表达，而 IL1RN 和 MMP9 在男性中高度表达， 母体表面存在相应的受体。二氢睾酮，仅由 男性胎儿中，除了 TGFβ1 和雌二醇外，还被确定为单个细胞中重要的上游调节因子 妊娠早期胎盘的类型。然而，荷尔蒙环境可能不是唯一的生物学性别 影响免疫系统的不同因素，因为我们还在早期发现了关键的转录调节因子 妊娠可能是免疫疾病的发育起源。 在整个生命周期中，激素在免疫功能障碍和免疫功能障碍中发挥着重要作用。 总体而言，女性自身免疫性疾病的患病率较高，例如 系统性红斑狼疮、类风湿性关节炎和多发性硬化症。然而男性更有可能发展 强直性脊柱炎。此外，与女性相比，男性哮喘患病率更高 童年时期，但性二态性的患病率在青春期后发生变化，这表明睾酮可能是 保护的。潜在的性别差异也会影响免疫系统。不过，发帖 青春期，荷尔蒙调节再次出现性别二态性，并且很难将性别分开 激素对免疫系统的影响是生物性别的一个功能，受性别的影响 这是由于外部影响。 因此，为了更好地了解生物性别在发育起源过程中的影响 免疫功能，包括激素环境的影响，我们打算识别性别特异性转录 妊娠早期胎盘中的监管特征。此外，由于性激素在体内不是二态性的。 童年早期，即青春期之前，我们打算更好地了解性别对发育的影响 在荷尔蒙影响之前免疫系统的差异，以确定性的关键驱动因素 免疫功能的二态性。我们的目标是确定免疫功能障碍的性别独特调节因子 最终被用作治疗免疫疾病的更个性化的方法。