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Mathematical Modeling of the Impacts of Prebiotic Dietary Intervention on Immunomodulation During Estrogen Deficiency

雌激素缺乏期间益生元饮食干预对免疫调节影响的数学模型

基本信息

批准号：
10593502
负责人：
Ashlee Nicole Ford Versypt
金额：
$ 21.43万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593502
关键词：
Address Affect Aging Animal Model Attenuated Blood Bone Marrow Cell Line Cells Complex Computer Models Data Data Set Dendritic Cells Dendritic cell activation Dietary Intervention Differential Equation Disease Estrogen deficiency Estrogens Exclusion Fermentation Flow Cytometry Future Gene Expression Profile Histology Homeostasis Hormones Immune Immune response Immune system Inflammatory Intervention Intestines Investigation Literature Lymphoid Tissue Measurement Mediating Methods Modeling Mucous Membrane Mus Oligosaccharides Osteoblasts Osteoclasts Osteoporosis Outcome Ovarian hormone Ovariectomy Peripheral Phenotype Physiological Play Population Postmenopausal Osteoporosis Prevention strategy Process Protein Analysis Regulation Regulatory T-Lymphocyte Response to stimulus physiology Role Sampling Signal Transduction Skeletal system Stimulus Supplementation System T cell differentiation T cell response T-Lymphocyte Techniques Testing Translating Volatile Fatty Acids Work bone bone cell bone loss bone resorbing activity cell type computer studies cost cytokine design dietary effector T cell experimental study gastrointestinal system gut microbiota hormone deficiency immunoregulation improved in silico in vivo insight intestinal barrier intestinal epithelium invention mathematical model microbiota microorganism peripheral blood prebiotics prevent programs response skeletal therapeutic target tool transcriptome sequencing transcriptomics treatment optimization treatment strategy

项目摘要

A growing body of evidence points to the gut-bone axis as a promising therapeutic target for postmenopausal osteoporosis. Ovarian hormone deficiency induces a gut microbiota-dependent shift in effector T cell populations (e.g., T helper 17 [Th17] and T regulatory [TREG] cells) within the gut and bone marrow that disrupt bone homeostasis and lead to bone loss. Although the gut microbiota is recognized for playing a critical role in this osteoimmunological response, little is known about the signaling of gut resident dendritic cells that translates these local effects into systemic T cell responses. Prebiotics such as oligosaccharides serve as substrates for microorganisms residing within the gut. Fermentation of oligosaccharides by gut microbiota yields metabolites that favorably affect intestinal epithelial cells lining the mucosa and immune cells within the gut lymphoid tissues. The investigation of the mechanisms of prebiotic-induced immune and bone responses has been met with experimental challenges, namely those encountered when studying the interactions between multiple physiological systems. In this R21 project, we propose to study the dendritic cell-mediated bone and T cell responses to estrogen deficiency and to B-galactooligosaccharides (B-GOS) prebiotic dietary invention in the periphery (bone and blood) and locally in the gut using a combination of in silico mathematical models and in vivo animal models. The mathematical model we will develop will focus on the interacting systems modulated by B-GOS and by estrogen through T cells and dendritic cells. The model will use differential equations to track immune cells, cytokines, hormones, and metabolites in the gut and peripheral blood and bone compartments. The model will build from our literature-informed preliminary model of the interactions in the gut-bone axis in response to dietary intervention and will be refined by comparison to the experimental data collected in the study, specifically adding the roles of dendritic cells, estrogen, and different T cell populations. In addition to protein analysis of the cytokines and metabolites obtained from in vivo studies, we will use computational deconvolution methods to infer cell type-specific transcriptional profiles from heterogeneous samples. The transcriptomics data is intended to provide more comprehensive immune response information than flow cytometry alone and to be exploratory of cellular interactions excluded from the preliminary computational model, e.g., dendritic cells. This project is designed to provide key data about the dendritic cell and T cell immune responses stimulated by dietary B-GOS supplementation in both intact and ovarian hormone deficient animal models. Successful completion of this project will yield a predictive mathematical model that can be used as a tool to explain possible mechanisms for how local gut stimuli and immune responses interact to yield peripheral phenotype changes, to inform the design of future experiments, and to identify critical control points within the gut-bone axis for designing and optimizing treatment strategies.

越来越多的证据表明，肠-骨轴是绝经后治疗的一个有希望的靶点