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Sex and stress hormones control adrenal gland macrophage development and function"

性激素和应激激素控制肾上腺巨噬细胞的发育和功能"

基本信息

批准号：
10629376
负责人：
Jesse Warren Williams
金额：
$ 43.43万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2022-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629376
关键词：
Acute Adipose tissue Adrenal Cortex Adrenal Glands Adult Aldosterone Animal Model Anti-Inflammatory Agents Arterial Fatty Streak Atherosclerosis Automobile Driving Blood Vessels Bone Marrow Cardiovascular Diseases Castration Cells Cholesterol Chronic Chronic stress Complement Consumption Corticosterone Cytoplasm Development Diet Disease Endocrine Epinephrine Fatty acid glycerol esters Female Gene Expression Genes Genetic Gonadal Steroid Hormones Growth Health Heterogeneity Homeostasis Hormones Human Hypertension Immune Immune response Immune system Immunity In Vitro Inflammation Inflammatory Response Knock-out Knockout Mice Knowledge Lipids Literature Macrophage Maintenance Maps Metabolic Diseases Modeling Morbidity - disease rate Mus Organ Ovariectomy Patients Phenotype Plasma Play Population Production Proliferating Role Severity of illness Source Steroid Receptors Steroids Stress System TREM2 gene Testing Tissues Work biological adaptation to stress blood glucose regulation cardiovascular disorder risk cofactor cold stress cold temperature combat conditional knockout constitutive expression cytokine experience feeding fighting high risk hormonal signals hormone therapy male monocyte mortality mouse model new therapeutic target novel novel strategies programs recruit response sensor sex sexual dimorphism single-cell RNA sequencing steroid hormone stressor systemic inflammatory response therapeutic development tissue repair transcriptomics translational approach uptake virtual

项目摘要

Project Summary/Abstract: Chronic stress promotes a systemic inflammatory response that contributes to cardiovascular and metabolic disease (CVD), and even acutely augmented stress can exacerbate disease severity. In humans, consumption of high fat/high cholesterol diet (HFD) is a common co-factor driving chronic stress responses. Understanding mechanisms controlling the stress-response and its association with CVD diseases, which are nearly ubiquitous and a leading cause of mortality, will allow for development of impactful translational approaches to fight against this understudied disease. The AG is the primary source for steroid hormones, corticosterone and aldosterone that are produced in the cortex. Elevated corticosterone modifies glucose homeostasis, immunity, and tissue remodeling. Our prior work using a cold-temperature stress model showed that cold-stress drives the promotion of monocyte egress from bone marrow and exacerbated atherosclerosis. Therefore, we sought to determine whether the local immune cells in the AG were also responding to stress responses, either through cold-exposure or HFD feeding. Interestingly, we observed accumulation of lipid within AG resident macrophages sitting adjacent to hormone-producing endocrine cells in models of atherosclerosis, hypertension, or acute cold challenge. Tissue resident macrophages are typically tissue repair cells and lipid accumulation is associated with anti-inflammatory phenotypes in macrophages. AG macrophages have not been thoroughly described in literature, and their function in response to hormone signals is unknown. Through our preliminary studies of WT mice (chow-diet fed with no overt stressors), we identified two primary populations of macrophages present in the AG. These populations showed a sexual dimorphism in the representation of macrophage subsets when comparing adult male versus female mice. Furthermore, through single cell RNA- seq profiling between male and female AG immune populations, we identified gene programs associated with AG resident macrophages and found constitutive expression of the lipid-sensor Trem2, which was found to increased on AG macrophages following chronic challenge, supporting a role in responding to lipid-hormones. Loss of Trem2 was associated with lipid accumulation in the AG and elevated circulating corticosterone levels in the absence of challenge. Together, these observations led to the overarching hypothesis AG resident macrophage maintenance is controlled by sex hormone production, and that AG macrophages sense steroid hormones during stress responses to dampen inflammation and promote tissue health. Our extensive experience in studying tissue macrophage development and function, along with the utilization of new animal models make our group ideal to test these novel concepts. If true, the implications of this study will identify new approaches to regulate systemic inflammation responses through the modulation of AG associated macrophages, which might complement current lipid-control approaches used for high-risk CVD patients.

项目总结/文摘: