Defining the interactions of senescent immune cells and skeletal cells

定义衰老免疫细胞和骨骼细胞的相互作用

• 批准号: 10424667
• 负责人: Sundeep Khosla
• 金额: $ 49.05万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10424667
• 关键词: Address; Adoptive Transfer; Age; Age-Related Bone Loss; Age-Related Osteoporosis; Aging; Animals; Apoptosis; Automobile Driving; Biological Markers; Bone Marrow; CDKN2A gene; Cell Aging; Cell model; Cells; Characteristics; Chromatin; Chronic Disease; Chronology; Coculture Techniques; Complement; Cytometry; DNA Damage; DNA Repair; Defect; Degenerative Disorder; Deterioration; ERCC1 gene; Etiology; Extracellular Matrix; Genetic; Genetic Models; Human; Immune; Immune system; In Vitro; Inflammation; Inflammatory; Intervention; LOX gene; Laboratories; Lead; Lymphoid Cell; Mediating; Mediator of activation protein; Modeling; Mus; Myeloid Cells; Organ; Osteocytes; Osteoporosis; Phenotype; Population; Premature aging syndrome; Proteins; Regulation; Repair Complex; Resistance; Role; Skeleton; Testing; Time; Tissues; Transgenic Mice; Up-Regulation; Work; age related; aged; bone; cell age; chemokine; cytokine; experimental study; functional decline; immunosenescence; in vivo; mouse model; neutrophil; new therapeutic target; novel; osteoimmunology; paracrine; premature; prevent; senescence; single-cell RNA sequencing; skeletal; telomere

Cellular senescence is now recognized as one of the fundamental aging mechanisms contributing to multiple age-related degenerative conditions, including osteoporosis. In previous studies, we have systematically identified senescent cells in the bone microenvironment and demonstrated a causal role for senescent cells in mediating age-related bone loss in mice. In recent studies, we used a novel transgenic mouse model, p16- LOX-ATTAC, capable of temporal- and cell-specific senescent cell clearance, and found that in contrast to global clearance of senescent cells using the (p16)-INK-ATTAC model, clearance specifically of senescent osteocytes only partially replicated the beneficial skeletal effects of global senescent cell clearance, suggesting an important role for other cells in the bone microenvironment (e.g., immune cells) in contributing to skeletal aging. In addition, in our previous work, we demonstrated a dramatic upregulation of the senescence- associated secretory phenotype (SASP) in bone marrow myeloid cells with aging, and more recent studies by our investigative team have shown that with aging, activated neutrophils can induce senescence in multiple tissues in a paracrine manner. Conversely, senescent cells are capable of attracting neutrophils, which then further propagate senescence to other cells. Collectively, these studies point to previously unexplored cross- talk between skeletal and immune cells, specifically in the context of cellular senescence. Thus, our central hypothesis is that senescence of immune cells contributes to skeletal deterioration and conversely, senescent skeletal cells attract and contribute to an inflammatory and/or senescent phenotype of immune cells. We will test this hypothesis by examining the effects of senescent immune cells on bone and in the reverse experiment, evaluating the effects of senescent skeletal cells on immune cells. Our proposed studies make use of novel mouse models: p16-LOX-ATTAC mice, developed in the Khosla/Monroe laboratory, which are capable of temporal- and cell-specific (when crossed with a Cre mouse) senescent cell clearance; and Ercc1-/fl mice, developed by Drs. Niedernhofer and Robbins (Co-Is), where we can induce a tissue-specific DNA repair defect leading to premature cellular senescence only in that tissue (e.g., immune or skeletal cells). Collectively, our studies will address a number of fundamental questions relevant to osteoimmunology: (1) What are the specific populations of bone marrow immune cells that undergo senescence with aging using strictly defined criteria for cellular senescence (rather than the much broader umbrella of “immunosenescence” that includes inflammatory, but not necessarily senescent cells); (2) Does chronological or premature aging of the immune system cause skeletal deterioration?; (3) Conversely, do senescent skeletal cells lead to senescence, or at least inflammation, in bone marrow immune cells and does this further propagate senescence to other skeletal cells and perhaps systemically?; and (4) What are the potential mediators of the cross-talk between senescent skeletal cells and senescent/inflammatory immune cells?

细胞衰老现在被认为是导致多种衰老的基本衰老机制之一。 与年龄相关的退行性疾病，包括骨质疏松症。在以前的研究中，我们系统地 鉴定了骨微环境中的衰老细胞，并证明了衰老细胞在骨微环境中的因果作用。 介导小鼠年龄相关的骨质流失。在最近的研究中，我们使用了一种新的转基因小鼠模型，p16- LOX-ATTAC，能够时间特异性和细胞特异性的衰老细胞清除，并发现与 使用（p16）-INK-ATTAC模型的衰老细胞的整体清除，衰老细胞的特异性清除 骨细胞仅部分复制了整体衰老细胞清除的有益骨骼效应，表明 其它细胞在骨微环境中的重要作用（例如，免疫细胞）在促进骨骼 衰老此外，在我们之前的工作中，我们证明了衰老的戏剧性上调- 相关的分泌表型（SASP）在骨髓髓样细胞与衰老，以及最近的研究， 我们的研究小组已经表明，随着年龄的增长，激活的中性粒细胞可以诱导多种细胞的衰老， 以旁分泌的方式。相反，衰老细胞能够吸引中性粒细胞， 进一步将衰老传播到其他细胞。总的来说，这些研究指出了以前未探索的交叉- 骨骼和免疫细胞之间的对话，特别是在细胞衰老的背景下。因此，我们的中央 一种假说认为，免疫细胞的衰老导致骨骼退化，相反， 骨骼细胞吸引并促成免疫细胞的炎性和/或衰老表型。我们将 通过检测衰老免疫细胞对骨骼的影响来验证这一假设， 实验，评估衰老骨骼细胞对免疫细胞的影响。我们提出的研究利用 新型小鼠模型：p16-LOX-ATTAC小鼠，在Khosla/门罗实验室开发， 时间特异性和细胞特异性（当与Cre小鼠杂交时）衰老细胞清除;和Ercc 1-/fl小鼠， 由Niedernhofer和Robbins博士（Co-Is）开发，我们可以诱导组织特异性DNA修复缺陷 导致仅在该组织中过早的细胞衰老（例如，免疫或骨骼细胞）。总体而言，我们 研究将解决一些与骨免疫学相关的基本问题：（1）具体是什么？ 使用严格定义的标准， 细胞衰老（而不是更广泛的“免疫衰老”，包括 炎性细胞，但不一定是衰老细胞）;（2）免疫系统的时间性或过早老化是否 系统导致骨骼退化？(3)相反，衰老的骨骼细胞会导致衰老，还是 最少的炎症，在骨髓免疫细胞，这是否进一步传播衰老到其他骨骼 细胞，也许是系统性的？以及（4）衰老细胞与衰老细胞之间的相互作用的潜在介质是什么？ 骨骼细胞和衰老/炎症免疫细胞？