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: 10687088
• 负责人: Margareta Pisarska
• 金额: $ 13.99万
• 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 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687088
• 关键词: ATAC-seq; 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; Rheumatoid Arthritis; Role; Sex Differences; Signal Transduction; Stanolone; Surface; Systemic Lupus Erythematosus; Testosterone; Transcriptional Regulation; Transforming Growth Factor beta; anakinra; biological sex; cell type; cytokine; differential expression; early childhood; fetal; gender difference; gene regulatory network; 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 孕产妇胎儿界面是激素和免疫学上富含免疫学的环境，对正常很重要 怀孕前三个月的胎盘。这也是成人疾病发育的地方 起源。在妊娠的这个阶段，马的和免疫学的环境已经是性二态的。 我们在全球和头三个月的单个细胞类型中鉴定了性二态基因表达 胎盘受到Mater胎儿界面的信号的影响，其中包括TGF-β超家族的成员 男性的TGFβ-1和BMP。在单个细胞类型中，CCL家族的配体最多 女性高度代表性，而IL1RN和MMP9在男性中高度表达 母体表面上存在的相应受体。二氢睾丸激素，仅由 除TGFβ1和雌二醇外，雄性胎儿被确定为单个细胞中的显着上游调节剂 头三个月的类型。但是，荷尔蒙环境可能不是唯一的生物学性爱 不同因素会影响免疫系统，因为我们还确定了早期的关键转录调节剂 妊娠可能解释了免疫疾病的发育起源。 在整个寿命中，激素被暗示在免疫功能障碍和 疾病的发展，因为总体而言，女性的自身免疫性疾病的患病率更高，例如 全身性红斑狼疮，类风湿关节炎和多发性硬化症。但是男人更有可能发展 强直性赞助。此外，与女性相比，男性的哮喘患病率增加 童年，但二态流行率变化，表明睾丸激素可能是 保护的。也存在影响免疫系统的潜在性别差异。但是，帖子 青春期，荷尔蒙调节再次变得二态，很难分开 马匹的影响是生物学性别的函数对性别影响的免疫系统的影响 这是由于外部影响。 因此，为了更好地了解在发育起源期间生物性别的影响 免疫功能，包括马利亚的效果，我们打算识别性别特定的转录 前三个月的监管签名。此外，由于性激素的性激素不在 童年，青春期之前，我们打算更好地了解性别对发展的影响 在激素影响之前，免疫系统的差异以识别性行为的关键驱动因素 免疫学中的二态性。我们的目标是确定性别独特的免疫学调节剂，可以 最终被用作治疗免疫疾病的一种更个性化的方法。

项目成果

High-throughput mRNA-seq atlas of human placenta shows vast transcriptome remodeling from first to third trimester.

人类胎盘的高通量 mRNA-seq 图谱显示从妊娠早期到晚期的巨大转录组重塑。

• DOI: 10.1101/2023.06.06.543972
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Gonzalez,TaniaL;Wertheimer,Sahar;Flowers,AmyE;Wang,Yizhou;Santiskulvong,Chintda;Clark,EkaterinaL;Jefferies,CarolineA;Lawrenson,Kate;Chan,JessicaL;Joshi,NikhilV;Zhu,Yazhen;Tseng,Hsian-Rong;Karumanchi,SAnanth;Williams,John