Deciphering hormonal regulation of neutrophil biology

破译中性粒细胞生物学的激素调节

基本信息

批准号：
10707917
负责人：
Berenice Anath Benayoun
金额：
$ 51.61万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
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/10707917
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 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 segregation sex sexual dimorphism single-cell RNA sequencing targeted treatment transcriptome transdifferentiation

项目摘要

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.

项目摘要/摘要尽管衰老是整个进化远处物种的保守现象，但生物学的关键方面在衰老期间，已经发现过程中的男性和女性之间的过程有所不同。例如，积累的证据表明，男性与女性的免疫细胞显然是不同的一生。尽管存在明显的差异及其潜在意义，但生物医学研究还是从历史上看，仅专注于男性。这是性驱动的差异，它们的分子对成人健康的各个方面的基础和影响，包括终身免疫复杂，仍然是理解不佳。有趣的是，性激素（即雄激素与雌激素）和性别染色体既有（即XX与XY）在繁殖和性腺发育之外具有关键影响。确实，积累证据支持生物学过程中宽度性二态性的概念。例如，免疫生物性别之间的反应不同，女性的免疫反应更强大与增加男性感染的敏感性。中性粒细胞是主要的白细胞种群，作为“ 防御感染感。我们已经观察到转录组，代谢组和鼠的嗜中性粒细胞的脂肪组，以及中性粒细胞介导的免疫型的变化。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学。我们假设涉及性染色体和终生暴露于性腺激素独立调节基于中性粒细胞的基因组网络和免疫表型一生。为了检验我们的假设，我们将研究中性粒细胞的基于中性粒细胞表型通过一生中的性函数进行微调。性激素和性染色体补体在野生型动物中密切相关，使确定性二态的研究变得复杂表型。为了解决这一缺点，我们将利用成人躯体性别的创新模型重新编程（成人FOXL2-IKO）评估荷尔蒙与遗传性别对中性粒细胞的影响一生的表型。这个独特且可进行的系统将使我们能够理解后果成年人暴露于较高水平的雌激素与雄激素对免疫反应的暴露。一起，我们提出了实验将提供有关免疫调节的性二态机制的见解，并揭示了如何马匹输入可能会对免疫细胞产生终生影响。