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

基本信息

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
项目类别：
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

项目摘要

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疾病的基本衰老机制之一在之前的研究中，我们系统地研究了与年龄相关的退行性疾病，包括骨质疏松症。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在最近的研究中，我们使用了一种新型转基因小鼠模型 p16- 介导与年龄相关的骨质流失。 LOX-ATTAC，能够清除时间和细胞特异性的衰老细胞，并发现与使用 (p16)-INK-ATTAC 模型全面清除衰老细胞，特别清除衰老细胞骨细胞仅部分复制了整体衰老细胞清除的有益骨骼效应，这表明骨微环境中的其他细胞（例如免疫细胞）在促进骨骼健康方面发挥着重要作用此外，在我们之前的工作中，我们证明了衰老的显着上调。骨髓髓样细胞与衰老相关的分泌表型（SASP），以及最近的研究我们的研究团队表明，随着衰老，活化的中性粒细胞可以诱导多种细胞衰老在离线组织中，衰老细胞能够吸引中性粒细胞，然后中性粒细胞总的来说，这些研究指出了以前未探索过的交叉作用。骨骼细胞和免疫细胞之间的对话，特别是在细胞衰老的背景下，因此，我们的中枢。假设免疫细胞的衰老会导致骨骼退化，反之，衰老的细胞会导致骨骼退化。骨骼细胞吸引并促进免疫细胞的炎症和/或衰老表型。通过检查衰老免疫细胞对骨骼的影响以及相反的影响来检验这一假设实验，评估衰老骨骼细胞对免疫细胞的影响。新型小鼠模型：p16-LOX-ATTAC 小鼠，由 Khosla/Monroe 实验室开发，能够时间和细胞特异性（与 Cre 小鼠杂交时）衰老细胞清除；和 Ercc1-/fl 小鼠，由 Niedernhofer 和 Robbins (Co-Is) 博士开发，我们可以诱导组织特异性 DNA 修复缺陷仅导致该组织（例如免疫细胞或骨骼细胞）的细胞过早衰老。研究将解决与骨免疫学相关的一些基本问题：（1）具体有哪些使用严格定义的标准，随着年龄的增长而经历衰老的骨髓免疫细胞群细胞衰老（而不是更广泛的“免疫衰老”，其中包括 (2) 免疫系统是否随时间老化或过早老化系统导致骨骼退化？；（3）离线，衰老的骨骼细胞导致衰老，还是在骨髓免疫细胞中的炎症最少，这是否会进一步将衰老传播到其他骨骼 (4) 衰老细胞之间的串扰有哪些潜在的中介因素？骨骼细胞和衰老/炎症免疫细胞？