Development of an Inducible Conditional Gene Deletion Mouse Model to Study Plasma Cell Development and Longevity

开发可诱导条件基因缺失小鼠模型来研究浆细胞发育和寿命

基本信息

批准号：
10705064
负责人：
Peter Dion Pioli
金额：
$ 5.35万
依托单位：
UNIVERSITY OF SASKATCHEWAN
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：
2022-09-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10705064
关键词：
Acute Myelocytic Leukemia Adopted Age Aging Animals Antibodies Antibody Formation Antibody Repertoire B cell differentiation B-Lymphocytes Behavior Biological Models Biological Process Blood Cells Bone Marrow Breeding Cell Count Cell Separation Cell surface Cells Cellular Assay Cellularity DNA Binding DNA Damage Deoxyuridine Derivation procedure Detection Development Disease Disparity Dose Elderly Enterobacteria phage P1 Cre recombinase Euthanasia Event Female Flow Cytometry Fluorescence Gene Deletion Generations Genes Genetic Recombination Glucose Health Hematopoietic Hematopoietic stem cells Human Humoral Immunities Immune response Incidence Individual Inflammation Inflammatory Label Link Longevity Maintenance Mature B-Lymphocyte Methods Modeling Mouse Protein Mus Myelogenous Myeloid Leukemia Myelopoiesis Permeability Phenotype Physiologic pulse Physiological Processes Plasma Cells Plasmablast Play Population Population Dynamics Process Production Proteins Protocols documentation Reporter Research Role Sex Bias Sex Differences Site Spleen System T-Lymphocyte Tamoxifen Techniques Technology Terminator Codon Testing Thymus Gland Time Work Youth adaptive immune response age related aged aging population cell age cell behavior experimental study glucose analog glucose uptake healthspan inducible Cre male mouse Cre recombinase mouse model plasma cell development progenitor prospective response sex sex disparity therapy development transcription factor vaccine response

Acute Myelocytic Leukemia Adopted Age Aging Animals Antibodies Antibody Formation Antibody Repertoire B cell differentiation B-Lymphocytes Behavior Biological Models Biological Process Blood Cells Bone Marrow Breeding Cell Count Cell Separation Cell surface Cells Cellular Assay Cellularity DNA Binding DNA Damage Deoxyuridine Derivation procedure Detection Development Disease Disparity Dose Elderly Enterobacteria phage P1 Cre recombinase Euthanasia Event Female Flow Cytometry Fluorescence Gene Deletion Generations Genes Genetic Recombination Glucose Health Hematopoietic Hematopoietic stem cells Human Humoral Immunities Immune response Incidence Individual Inflammation Inflammatory Label Link Longevity Maintenance Mature B-Lymphocyte Methods Modeling Mouse Protein Mus Myelogenous Myeloid Leukemia Myelopoiesis Permeability Phenotype Physiologic pulse Physiological Processes Plasma Cells Plasmablast Play Population Population Dynamics Process Production Proteins Protocols documentation Reporter Research Role Sex Bias Sex Differences Site Spleen System T-Lymphocyte Tamoxifen Techniques Technology Terminator Codon Testing Thymus Gland Time Work Youth adaptive immune response age related aged aging population cell age cell behavior experimental study glucose analog glucose uptake healthspan inducible Cre male mouse Cre recombinase mouse model plasma cell development progenitor prospective response sex sex disparity therapy development transcription factor vaccine response

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项目摘要

Project Summary/Abstract Aging is associated with an overall decline in the adaptive immune response with a bulk of the research focusing on the deficiencies surrounding not only the function, but also the generation, of naive B and T lymphocytes. In contrast, not much is known about how aging alters the functionality of plasmacytes. Plasmacytes represent the terminal differentiation step of mature B cells and consist of both short-lived, proliferative plasmablasts (PBs) and more mature, non-proliferative plasma cells (PCs). These cells are key facilitators of humoral immunity through their robust production of antibodies (Abs) as well as their potential to be long-lived. In humans, this longevity can span decades. Historically, these cells have been considered nothing more than Ab factories; however, recent work has demonstrated the ability of plasmacytes to regulate a variety of physiological processes. In the context of aging, PCs have been shown to evolve a pro-inflammatory phenotype and be key drivers of the increased bone marrow (BM) myelopoiesis normally observed in the elderly. This is in part through the PC-dependent expansion in the numbers of hematopoietic stem cells and myeloid progenitors which has been linked to the elevated incidence of myeloid leukemias in the aged population. More recently, we have identified a sex disparity that exists in regard to PB/PC populations within the young thymus (THY) in which 3 months old female mice have significantly higher numbers of these cells compared to males. Interestingly enough, these THY PBs/PCs express key proteins required for THY T cell selection and their numbers significantly correlate with overall THY cellularity. Similar to BM, we have observed changes in THY PB/PC populations in the context of aging. In particular, male mice accumulate THY PBs/PCs with age while numbers remain constant in females. This is in contrast to BM and spleen (SPL) where PBs/PCs increase with age in both sexes. Thus, understanding how PBs/PCs age will allow us to better evaluate their role(s) in adaptive immune responses in the elderly as well as their evolving repertoire of Ab-independent functions. Ultimately, this may lead to the development of therapies that alter PB/PC behavior and promote increased healthspan in aged individuals. It is currently difficult to identify bona fide long-lived, or aged, plasmacytes. While a variety of cell surface markers have been shown to identify plasmacytes, these determinants do not necessarily correlate with longevity but rather maturity. Alternatively, cell labeling techniques rely on efficient labeling of upstream B cells and label retention in the subsequently generated PBs/PCs. In some instances, detection of these labels requires cell permeabilization thus eliminating the ability to further study living, aged PBs/PCs. Aim 1 focuses on the development of an inducible system to indelibly mark, or timestamp, plasmacytes using a fluorescence reporter thus facilitating the ability to assess population dynamics and potentially isolate cells of various ages. Aim 2 will demonstrate the feasibility of this reporter system to specifically determine differential population turnover and/or maintenance in female versus male THY plasmacytes.