Modeling of HIF-1-alpha Regulation of B Cell Migration

B 细胞迁移的 HIF-1-α 调节建模

基本信息

批准号：
10161716
负责人：
Shannon Hilchey
金额：
$ 74.04万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-06 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10161716
关键词：
Affect Anatomy Antibodies B-Cell Activation B-Lymphocytes Biology Bone Marrow CRISPR/Cas technology CXCR4 Receptors CXCR4 gene Calcineurin Calcineurin Pathway Calcineurin inhibitor Cell physiology Chemotaxis Coupled Cyclosporine DNA Binding Domain Data Ethics Functional disorder Generations Genomics HIF1A gene Human Hypoxia Immune response Immunocompromised Host Immunosuppression Immunosuppressive Agents In Vitro Individual Infection Intervention Link Location Lymphocyte Measurement Measures Mediating Modeling Molecular Mus Mutagenesis Mutate Nodal Oxygen Pathway interactions Patients Peripheral Pharmaceutical Preparations Physiologic pulse Process Procollagen-Proline Dioxygenase Proteins Proteome Proteomics Reaction Receptor Signaling Regulation Resolution Risk Role Signal Transduction Signaling Protein Site Structure of germinal center of lymph node Surveys System Systemic infection Systems Biology Testing Time Transcript Transplant Recipients Vaccination Validation Work antigen challenge cell motility chemokine receptor clinical application draining lymph node experimental study human migration hypogammaglobulinemia immunosuppressed improved in vivo inhibitor/antagonist knock-down lymph nodes migration molecular modeling mouse model peripheral blood plasma cell differentiation predictive modeling premature prevent receptor sensitivity response secondary lymphoid organ sensor small hairpin RNA small molecule small molecule inhibitor therapeutic target tissue culture trafficking transcription factor transcriptome transcriptomics vaccine efficacy vaccine response

项目摘要

Project Summary Characterization of primary human immune responses to infection or vaccination often relies on surveying peripheral lymphocytes, as access to the sites where primary responses occur, such as the draining lymph nodes (LN), are not readily accessible due to anatomical location and ethical considerations. Thus, the majority of studies examining human B cell activation and plasma cell differentiation are performed in vitro under normoxic tissue culture conditions. However, B cells are activated, differentiate, within the low oxygen germinal center of the lymph node, and subsequently migrate from one anatomical compartment to another, where they encounter differing compartmental oxygen levels, ranging from 1-5% in the lymph node to 5-13% in the peripheral blood. The effects that oxygen levels have on B cells during an active immune response, in particular migration, is unknown. We hypothesize that oxygen tension is a previously unrecognized B cell regulatory switch, altering chemokine receptor signaling and controlling B cell migration. To test this hypothesis we propose the following specific Aims. Aim 1: Define and model the transcriptome and proteome pathways responsible for O2 dependent functional changes in B cell migratory capacity. Aim 2: Model the overlapping transcriptome and proteome pathways responsible for calcineurin perturbation of the HIF-1α molecular switch in human B cells. Aim 3: To assess the in vivo impact HIF-1α stabilization has on vaccine efficacy in a mouse model of immune suppression. The proposed work is intended to fill a critical gap in our understanding of human B cell responses, specifically the quantitative effects differing oxygen levels have on B cells migration.

项目摘要对原发性免疫调查的表征感染或疫苗接种通常依赖于测量外周淋巴细胞，作为对主要反应的位点的访问，例如排水淋巴由于解剖位置和道德考虑，节点（LN）不容易访问。那是大多数研究人B细胞激活和浆细胞分化的研究在体外进行常氧组织培养条件。但是，在低氧生发中激活B细胞，分化淋巴结的中心，随后从一个解剖区迁移到另一个解剖区室，遇到不同的室氧气水平，从淋巴结中的1-5％到5-13％外周血。氧气水平对活性免疫激发期间B细胞的影响，特别是迁移，未知。我们假设氧张力是先前未识别的B细胞调节开关，改变趋化因子受体信号传导和控制B细胞迁移。为了检验这一假设建议以下特定目标。 AIM 1：定义并建模转录组和蛋白质组途径负责B细胞迁移能力的O2依赖性功能变化。目标2：建模重叠负责HIF-1α分子开关的钙调神经蛋白扰动的转录组和蛋白质组途径人类B细胞。目标3：评估体内影响HIF-1α稳定对小鼠疫苗效率的稳定性拟议的工作旨在填补我们对人B细胞反应，特别是区分氧水平对B细胞迁移的定量效应。