Deciphering hormonal regulation of neutrophil biology

项目摘要/摘要 尽管衰老在进化的遥远物种中是一种保守的现象，但生物学的关键方面 已经发现，在同一物种的雄性和雌性之间，衰老的过程是不同的。例如, 越来越多的证据表明，男性和女性的免疫细胞明显不同。 在一生中。尽管有这些明显的差异和潜在的意义，生物医学研究 历史上只关注男性个体。因此，性别驱动的差异，他们的分子 对成人健康的各个方面的支持和影响，包括终身免疫反应，仍然是 人们对此知之甚少。有趣的是，性激素(即雄激素与雌激素)和性染色体 (例如，XX与XY)在生殖和性腺发育之外具有关键影响。的确，不断积累 有证据支持生物过程中普遍存在的性别二态现象。例如，免疫 生物性别之间的反应不同，女性的免疫反应更强，而女性的免疫反应更强 男性易受感染。中性粒细胞是一种主要的白细胞群体，它是 防御“感染。我们观察到在转录组、代谢组和 小鼠中性粒细胞的脂质体，以及中性粒细胞介导的免疫表型的变化。在一起，我们的 结果表明，涉及性腺激素和/或性染色体的机制可以调节 以中性粒细胞为基础的免疫。我们假设涉及性染色体和 终生接触性腺激素独立调节中性粒细胞基因组网络 以及一生中的免疫表型。为了验证我们的假设，我们将调查中性粒细胞是如何 在一生中，表型会随着性别的变化而发生微调。性激素与性染色体 补体在野生型动物中紧密相连，使性别二型性决定因素的研究复杂化 表型。为了解决这一缺陷，我们将利用一种创新的成人躯体性行为模式 重新编程(成人FOXL2-IKO)以评估荷尔蒙与遗传性别对中性粒细胞的影响 一生中的表型。这一独特且易于处理的系统将使我们能够了解其后果 成人暴露在较高水平的雌激素与雄激素对免疫反应的影响。一起，我们的建议 实验将提供关于免疫调节的性别二态机制的见解，并揭示如何 荷尔蒙的输入可能对免疫细胞产生终生影响。

Project Summary/Abstract Although aging is a conserved phenomenon across evolutionary distant species, key aspects of biological process have been found to differ between males and females of the same species during aging. For instance, accumulating evidence suggests that immune cells of male vs. female individuals are clearly distinct throughout life. Despite these clear differences and their potential significance, biomedical research has historically focused exclusively on male individuals. Thus, sex- driven differences, their molecular underpinning and impact on various aspects of adult health, including lifelong immune responses, are still poorly understood. Interestingly, both sex hormones (i.e. androgens vs. estrogens) and sex-chromosomes (i.e. XX vs. XY) have key impact outside of reproduction and gonadal development. Indeed, accumulating evidence supports the notion of widespread sex-dimorphism in biological processes. For example, immune responses differ between biological sexes, with a more robust immune response in females vs. increased susceptibility to infection in males. Neutrophils are a major leukocyte population serving as a “first line of defense” against infections. We have observed strong sex-dimorphism in the transcriptome, metabolome and lipidome of murine neutrophils, as well as changes in neutrophil-mediated immune phenotypes. Together, our results suggest that mechanisms involving gonadal hormones and/or sex chromosomes can regulate neutrophil-based immunity. We hypothesize that mechanisms involving both sex chromosomes and lifelong exposure to gonadal hormones independently modulate neutrophil-based genomic networks and immune phenotypes throughout life. To test our hypothesis, we will investigate how neutrophil-based phenotypes are fine-tuned as a function of sex throughout life. Sex hormones and sex chromosome complement are intimately linked in wild-type animals, complicating the study of determinants of sex-dimorphic phenotypes. To address this shortcoming, we will leverage an innovative model of adult somatic-sex reprogramming (the adult Foxl2-iKO) to assess the impact of hormonal vs. genetic sex on neutrophil phenotypes throughout life. This unique and tractable system will enable us to understand the consequences of adult exposures to higher levels of estrogens vs. androgens on immune responses. Together, our proposed experiments will provide insights on sex-dimorphic mechanisms of immune regulation and reveal how hormonal inputs may exert lifelong impact on immune cells.