Deciphering hormonal regulation of neutrophil biology

破译中性粒细胞生物学的激素调节

• 批准号: 10412518
• 负责人: Berenice Anath Benayoun
• 金额: $ 54.58万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412518
• 关键词: Address; Adult; Aging; Androgens; Animals; Biological; Biological Process; Biology; Biomedical Research; Cells; Chromatin; Chromosomes; Complex; Data; Development; Disease; Distant; Estrogens; Estrus; Exposure to; FOXL2 gene; Female; Gene Expression; Genetic; Genomics; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Health; Hormonal; Human; Immune; Immune System Diseases; Immune response; Immunity; Individual; Infection; Knowledge; Leukocytes; Life; Light; Link; Lipids; Mediating; Mediator of activation protein; Microfluidics; Modeling; Molecular; Mus; Ovary; Phenotype; Ploidies; Population; Predisposition; Process; Reproduction; Research; Resolution; Role; Sex Bias; Sex Chromosomes; Sex Differences; Shapes; System; Testing; Testis; Testosterone; Time; age related; antimicrobial; base; biological sex; cell type; experimental study; functional decline; genotypic sex; gonad development; health disparity; hormone regulation; immunoregulation; individualized medicine; innovation; insight; lipidome; machine learning model; male; metabolome; neutrophil; personalized medicine; sex; sexual dimorphism; single-cell RNA sequencing; targeted treatment; transcriptome; transdifferentiation

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.

项目概要/摘要 尽管衰老是进化遥远物种中的一种保守现象，但生物学的关键方面 人们发现，同一物种的雄性和雌性在衰老过程中的过程有所不同。例如， 越来越多的证据表明，男性和女性个体的免疫细胞明显不同 一生。尽管存在这些明显的差异及其潜在意义，但生物医学研究已经 历史上只关注男性个体。因此，性别驱动的差异，它们的分子 对成人健康各个方面（包括终生免疫反应）的基础和影响仍然存在 不太了解。有趣的是，性激素（即雄激素与雌激素）和性染色体 （即 XX 与 XY）在生殖和性腺发育之外具有重要影响。确实，积累 证据支持生物过程中广泛存在的性别二态性的概念。例如，免疫 生物性别之间的反应有所不同，女性的免疫反应比男性的免疫反应更强 男性易受感染。中性粒细胞是主要的白细胞群，充当“一线” 对感染的“防御”。我们观察到转录组、代谢组和 小鼠中性粒细胞的脂质组，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 基于中性粒细胞的免疫。我们假设涉及性染色体和 终生接触性腺激素独立调节基于中性粒细胞的基因组网络 和终生的免疫表型。为了检验我们的假设，我们将研究中性粒细胞如何 在一生中，表型会根据性别进行微调。性激素和性染色体 补体在野生型动物中密切相关，使性别二态性决定因素的研究复杂化 表型。为了解决这个缺点，我们将利用成人躯体性交的创新模型 重编程（成人 Foxl2-iKO）以评估激素与遗传性别对中性粒细胞的影响 贯穿一生的表型。这个独特且易于处理的系统将使我们能够理解后果 成人暴露于较高水平的雌激素与雄激素对免疫反应的影响。我们共同提出的 实验将提供对免疫调节的性别二态性机制的见解，并揭示如何 激素输入可能对免疫细胞产生终生影响。