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 母胎界面是激素和免疫丰富的环境，对于正常的 在怀孕的头三个月胎盘形成。这也是成人疾病在发展过程中 起源.在妊娠的这一阶段，激素和免疫环境都已经是两性异形的了。 我们发现，在妊娠的前三个月， 胎盘受到母体胎儿界面信号传导的影响，包括TGF-β超家族成员， 特别是TGFβ-1和BMP。在单个细胞类型中，来自CCL家族的配体最多。 在女性中高度代表性，而IL 1 RN和MMP 9在男性中高度表达， 相应的受体存在于母体表面。双氢睾酮，这是唯一产生的 除了TGFβ1和雌二醇外，男性胎儿也被确定为单个细胞中重要的上游调节因子。 第一孕期胎盘的类型。然而，荷尔蒙环境可能不是唯一的生物性别， 不同的因素影响免疫系统，因为我们还确定了关键的转录调节因子在早期 妊娠可能是免疫性疾病的发育起源。 在整个生命周期中，激素被认为在免疫功能障碍中起重要作用， 疾病的发展，因为总体而言，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，男性更有可能发展为 强直性脊柱炎此外，与女性相比， 儿童期，但性二态患病率在青春期后发生变化，这表明睾酮可能是 保护性的还有潜在的性别差异会影响免疫系统。然而，Post 在青春期，荷尔蒙调节再次变得性二态化，并且很难将 激素的影响，这是一个功能的生物性别对免疫系统的影响， 这是由于外部的影响。 因此，为了更好地理解生物性别在发育起源中的影响， 免疫功能，包括激素环境的影响，我们打算确定性别特异性转录 在妊娠早期胎盘中的调节信号。此外，由于性激素在体内不是二态的， 在青春期之前的儿童早期，我们打算更好地了解性别对发育的影响， 免疫系统的差异，在激素影响之前，以确定性行为的关键驱动因素。 免疫功能的二型性。我们的目标是确定免疫功能障碍的性别独特调节因子， 最终将被用作治疗免疫性疾病的更个性化的方法。