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.

项目总结/文摘