Effects of Age-Related Changes in the Microenvironment on Patterns of Hematopoiesis

与年龄相关的微环境变化对造血模式的影响

基本信息

批准号：
9364678
负责人：
KENNETH Allan DORSHKIND
金额：
$ 31.78万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9364678
关键词：
Active Sites Adipocytes Affect Age Aging Alpha Cell Animals Antibodies B cell repertoire B-Cell Development Birth Blood Cells Bone Marrow Cells Complement Data Development Elderly Gene Expression Profile Generations Genetic Models Goals Hematopoiesis Hematopoietic Hematopoietic stem cells High Fat Diet Immune system Immunity Immunoglobulin-Secreting Cells Impairment In Vitro Individual Infection Inflammation Mediators Inflammatory Interleukin-1 Interleukin-1 Receptors Intervention Life Light Literature Lymphocyte Lymphoid Lymphoid Cell Lymphopoiesis Measures Modeling Mus Myelogenous Myeloid Cells Myelopoiesis Pattern Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Pharmacology Plasma Cells Population Predisposition Process Production Red Marrow Rejuvenation Resistance Signal Transduction Source Stromal Cells System Testing Time Vaccination Yellow Marrow age effect age related cohesion cytokine environmental change expectation experimental study impaired capacity in vivo insight interest novel prevent response transcriptome

项目摘要

Abstract Hematopoiesis is often viewed as a uniform process in which lymphoid and myeloid cells are continually generated in constant proportions throughout life. It is now evident that this is not the case and that, with increasing age, there is a decline in B cell development while myelopoiesis remains relatively intact. This in turn is thought to contribute to the increased susceptibility of the elderly to infection and the reduced efficacy of vaccination. The central hypothesis of this proposal is that the age-related accumulation of adipocytes and plasma cells in the medullary cavity impairs the capacity of the hematopoietic microenvironment to support lymphopoiesis. In contrast, myelopoiesis is either resistant to or is stimulated by these changing environmental dynamics. At birth most of the bone marrow is referred to as “red” marrow to indicate that it is a site of active hematopoiesis. However, with increasing age there is an accumulation of adipocytes and the formation of non- hematopoietic “yellow” marrow. The accumulation of bone marrow adipocytes is a gradual process, and we propose that as this occurs, lymphopoiesis is preferentially inhibited while myelopoiesis remains relatively intact. Experiments in Aim 1 will test this hypothesis using both in vivo and in vitro systems, and we will also analyze patterns of hematopoiesis in PPAR-γ+/– mice, which have a highly significant diminution in bone marrow adipocytes, over time. The expectation is that age-related declines in B lymphopoiesis will be less severe in this strain due to their adipocyte deficiency. Bone marrow adipocytes provide a supportive niche for plasma cells. In view of their increase in number with age, we considered the possibility that plasma cells might also increase over time and found this to be the case. This has significant implications, as plasma cells are a source of numerous inflammatory cytokines known to inhibit B lymphopoiesis. Experiments in Aim 2 will test the hypothesis that this increase in plasma cells also contributes to age-related reductions in lymphocyte development. We will build upon preliminary data showing that plasma cells co-localize with hematopoietic stem cells (HSCs) in the bone marrow and evaluate the potential of plasma cell derived signals to skew the developmental potential of HSCs towards myelopoiesis. We will also generate Cd19-Cre;flPrdm1fl mice which lack plasma cells and determine if declines in B lymphopoiesis in these animals are less precipitous over time. A key question from a translational perspective is whether lymphopoiesis can be rejuvenated in old individuals. The experiments in Aim 3 will test the ability of various interventions, which include drugs that inhibit adipocyte formation and antibodies that deplete plasma cells, to rejuvenate B lymphopoiesis in the elderly. Additional experiments will determine if these interventions target HSCs and affect patterns of gene expression in them. Taken together, the data obtained in the proposed studies will increase the understanding of how aging affects hematopoiesis and identify interventional targets that may have translational potential for rejuvenating immunity in the elderly.

抽象的造血通常被视为一个统一的过程，其中淋巴和骨髓细胞不断地现在很明显，情况并非如此，并且在整个生命中以恒定的比例产生。随着年龄的增长，B 细胞发育会下降，而骨髓生成却相对完整。据认为，这会导致老年人对感染的易感性增加，并降低治疗效果该提案的中心假设是脂肪细胞的积累与年龄相关。髓腔中的浆细胞损害造血微环境支持的能力相反，骨髓生成要么抵抗这些变化的环境，要么受到这些变化的刺激。出生时，大部分骨髓被称为“红”骨髓，表明它是一个活跃的部位。然而，随着年龄的增长，脂肪细胞会积累并形成非细胞。造血“黄”骨髓。骨髓脂肪细胞的积累是一个渐进的过程，我们提出当这种情况发生时，淋巴细胞生成优先受到抑制，而骨髓生成保持相对完整。目标 1 中的实验将使用体内和体外系统来检验这一假设，我们还将分析 PPAR-γ+/– 小鼠的造血模式，其骨髓显着减少随着时间的推移，预计脂肪细胞中与年龄相关的 B 淋巴细胞生成下降将不会那么严重。由于脂肪细胞缺乏，骨髓脂肪细胞为浆细胞提供了支持性生态位。鉴于它们的数量随着年龄的增长而增加，我们考虑了浆细胞也可能增加的可能性随着时间的推移，我们发现这具有重大意义，因为浆细胞是细胞的来源。目标 2 中的许多已知抑制 B 淋巴细胞生成的炎症细胞因子将检验这一假设。浆细胞的增加也会导致淋巴细胞发育与年龄相关的减少。初步数据表明浆细胞与造血干细胞（HSC）共定位于骨髓并评估浆细胞衍生信号影响骨髓发育潜力的潜力我们还将生成缺乏浆细胞的 Cd19-Cre;flPrdm1fl 小鼠。确定这些动物的 B 淋巴细胞生成能力的下降是否随着时间的推移而不再急剧下降。转化视角是老年个体的淋巴细胞生成是否可以恢复活力。 Aim 的实验。 3将测试各种干预措施的能力，其中包括抑制脂肪细胞形成的药物和抗体进一步的实验将确定是否可以消耗浆细胞，从而恢复老年人的 B 淋巴细胞生成能力。这些干预措施针对 HSC 并影响其中的基因表达模式。在拟议的研究中获得的结果将增加对衰老如何影响造血的理解，并确定干预目标可能具有恢复老年人免疫力的转化潜力。