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: 10629252
• 负责人: Sundeep Khosla
• 金额: $ 47.57万
• 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/10629252
• 关键词: Acceleration; 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 Senescence Induction; Cell Separation; 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; Interphase Cell; Intervention; LOX gene; Laboratories; Lead; Lymphoid Cell; Mediating; Mediator; Modeling; Mus; Myeloid Cells; Organ; Osteocytes; Osteoporosis; Phenotype; Population; Premature aging syndrome; Proliferating; 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; stressor; 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?

现在，细胞感应被认为是促成多种的基本衰老机制之一 与年龄相关的退化条件，包括骨质疏松症。在先前的研究中，我们有系统地 确定了骨微环境中的感觉细胞，并证明了感觉细胞在 介导小鼠年龄相关的骨质流失。在最近的研究中，我们使用了一种新型的转基因小鼠模型P16- Lox-Attac，能够具有临时和细胞特异性的感觉细胞清除率，发现与 使用（p16）-ink-attac模型对感觉细胞的全球清除率，特别是senscent的清除率 骨细胞仅部分复制了全球感觉细胞清除的有益骨骼效应，这表明 其他细胞在骨微环境（例如免疫细胞）中的重要作用在有助于骨骼 老化。此外，在我们以前的工作中，我们证明了感应 - 与衰老的骨髓髓样细胞中的相关秘密表型（SASP），以及最近的研究 我们的调查团队表明，随着老化，激活的中性粒细胞可以诱导多种 以旁分泌方式组织。相反，感觉细胞能够吸引中性粒细胞，然后 进一步向其他细胞传播感应。这些研究共同指出了以前出乎意料的交叉 骨骼和免疫细胞之间的交谈，特别是在细胞感应的背景下。那，我们的中心 假设是免疫电池的感应有助于骨骼定义，相反，感觉 骨骼细胞吸引并有助于免疫细胞的炎症和/或感觉表型。我们将 通过检查感觉免疫细胞对骨骼和反向的影响来检验该假设 实验，评估感觉骨骼细胞对免疫细胞的影响。我们提出的研究使用 新型小鼠模型：在Khosla/Monroe实验室中开发的P16-Lox-Attac小鼠，它们能够 临时和细胞特异性（与CRE小鼠交叉时）感觉细胞清除率；和Ercc1-/fl小鼠， 由Drs开发。 Niedernhofer和Robbins（CO-IS），我们可以诱导组织特异性的DNA修复缺陷 仅在该组织（例如免疫或骨骼细胞）中导致过早的细胞感应。总体而言，我们的 研究将解决与骨气免疫学相关的许多基本问题：（1）具体是什么 骨髓免疫细胞的群体，使用严格定义的标准衰老会受到衰老的感受 细胞感应（而不是“免疫衰老”的更宽的雨伞，包括 炎症，但没有必要的感官细胞）； （2）免疫的时间顺序或过早衰老 系统引起骨骼定义？ （3）相反，DO骨骼细胞会导致感受，或者在 在骨髓免疫细胞中炎症最少，并进一步传播到其他骨骼 细胞，也许是系统的？ （4）Senscent之间的串扰的潜在介体是什么 骨骼细胞和感觉/炎症免疫力？