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

• 批准号: 10207432
• 负责人: KENNETH Allan DORSHKIND
• 金额: $ 31.98万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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/10207432
• 关键词: Active Sites; Adipocytes; Affect; Age; Aging; 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; PPAR gamma; Pattern; Pharmaceutical Preparations; Pharmacology; Plasma Cells; Population; Predisposition; Process; 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

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 造血经常被视为一个均匀的过程，其中淋巴样和髓样细胞是连续的 一生中不断产生。现在有证据表明事实并非如此，并且 随着年龄的增长，B细胞发育的下降，而骨髓病变保持相对完整。反过来 被认为有助于提高老年感染的敏感性以及降低的效率 疫苗接种。该提议的核心假设是脂肪细胞与年龄相关的积累 髓液中的浆细胞会损害造血微环境的能力 淋巴虫性。相比之下，骨髓虫具有对这些不断变化的环境的抵抗力或刺激 动力学。在出生时 造血。但是，随着年龄的增长，脂肪细胞的积累和非 - 造血“黄”骨髓。骨髓脂肪细胞的积累是一个分级过程，我们 提出的建议是，淋巴细胞症优选地抑制，而骨髓疫异常相对完整。 AIM 1中的实验将使用体内和体外系统测试这一假设，我们还将分析 PPAR-γ+/小鼠中造血的模式，在骨髓中具有极高的显着降低 脂肪细胞，随着时间的流逝。期望与年龄相关的B淋巴细胞减少在此不那么严重 由于其脂肪细胞缺乏而应变。骨髓脂肪细胞为浆细胞提供了支持的利基市场。在 它们随着年龄的增长而增加的观点，我们认为浆细胞也可能增加 随着时间的流逝，情况就是如此。这具有重要的含义，因为浆细胞是 已知可抑制B淋巴细胞的许多炎性细胞因子。 AIM 2中的实验将检验假设 浆细胞的增加也有助于与年龄相关的淋巴细胞发育减少。我们将 基于初步数据，表明浆细胞与造血干细胞（HSC）共定位 骨髓并评估浆细胞衍生信号的潜力，以使 HSC朝向脊髓虫。我们还将生成缺乏浆细胞和 确定随着时间的流逝，这些动物中B淋巴细胞的下降是否降低。来自 翻译的观点是，淋巴管是否可以在老个人中恢复活力。 AIM中的实验 3将测试各种干预措施的能力，其中包括抑制脂肪细胞和抗体的药物 这样可以复制浆细胞，以使B淋巴管恢复原状。其他实验将确定是否 这些干预措施针对HSC并影响其中基因表达的模式。总之，数据 在拟议的研究中获得的将增加对衰老如何影响造血的理解并确定 介入的目标可能转化了恢复较早免疫力的潜力。

项目成果

Do haematopoietic stem cells age?

• DOI: 10.1038/s41577-019-0236-2
• 发表时间: 2020-03
• 期刊: Nature reviews. Immunology
• 作者: Dorshkind K;Höfer T;Montecino-Rodriguez E;Pioli PD;Rodewald HR
• 通讯作者: Rodewald HR

AMYQ: An index to standardize quantitative amyloid load across PET tracers.

• DOI: 10.1002/alz.12317
• 发表时间: 2021-09
• 期刊: Alzheimer's & dementia : the journal of the Alzheimer's Association
• 作者: Pegueroles J;Montal V;Bejanin A;Vilaplana E;Aranha M;Santos-Santos MA;Alcolea D;Carrió I;Camacho V;Blesa R;Lleó A;Fortea J;Alzheimer Disease Neuroimaging Initiative;Australian Imaging, Biomarkers and Lifestyle Research Group
• 通讯作者: Australian Imaging, Biomarkers and Lifestyle Research Group