Aging and dysfunction of progenitor niches: Role of Del-1

祖细胞生态位的衰老和功能障碍：Del-1 的作用

• 批准号: 10536596
• 负责人: Georgios Hajishengallis
• 金额: $ 33.42万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10536596
• 关键词: Address; Affect; Age; Age Months; Aging; Animal Model; Apoptotic; Area; Back; Biological Assay; Biology; Bone Regeneration; Bone Tissue; Cells; Chronic; Collaborations; Defect; Development; Disease; Elderly; Endothelial Cells; Endothelium; Functional disorder; Genetic; Germany; Homeostasis; Human; ITGB3 gene; Immune response; Immunity; Impairment; In Vitro; Inflammation; Inflammatory; Integrins; Intervention Studies; Investments; Knock-out; Leukocytes; Location; MAPK3 gene; Macrophage; Mesenchymal; Mesenchymal Stem Cells; Modeling; Molecular; Mus; Neutrophil Infiltration; Osteogenesis; PTK2 gene; Paper; Pennsylvania; Periodontal Diseases; Periodontal Ligament; Periodontitis; Periodontium; Predisposition; Prevalence; Process; Proliferating; Protein Secretion; Proteins; Psychiatry; Publications; RGD (sequence); Regenerative capacity; Rejuvenation; Research; Resolution; Role; Severities; Signal Transduction; Source; Testing; Therapeutic; Tissues; Tooth structure; Transgenic Organisms; Universities; Work; age related; aged; alveolar bone; bone loss; experimental study; human old age (65+); immunoregulation; improved; in vivo; in vivo Model; insight; mutant; neutrophil; novel; osteoblast differentiation; osteogenic; osteoprogenitor cell; overexpression; progenitor; receptor; recruit; regeneration potential; regenerative; repaired; stem cell niche; stem cell self renewal; stem cells; tissue regeneration; tissue repair; tool; transcription factor

Project Summary The elderly have increased susceptibility to periodontitis, a prevalent inflammatory disease that causes destruction of the tooth-supporting tissues (periodontium). This increased susceptibility is likely caused by alterations to the immuno-inflammatory status and/or regenerative potential of the periodontal tissue. Impaired tissue regeneration may be traced back to age-related alterations in the mesenchymal stem cell (MSC) niche of the periodontal ligament (PDL), harboring the osteoprogenitors. Del-1 is a homeostatic protein secreted by distinct tissue resident cells: It regulates the recruitment of neutrophils (endothelial cell-derived Del-1) and the efferocytosis of apoptotic neutrophils (macrophage-derived Del-1), thus Del-1 controls both the initiation and resolution of inflammation. Additional research has shown that Del-1 is produced in the PDL and promotes osteoblastic differentiation as well as induces the formation of new alveolar bone during resolution of experimental periodontitis. However, Del-1 expression is severely diminished in old age. This project investigates the overarching hypothesis that the aging-related Del-1 deficiency may contribute to the dysregulation of osteogenesis, thereby leading to defective periodontal bone regeneration in old age. This proposal comprises two specific aims and focuses on relevant animal model-based mechanistic and intervention studies, including mice with lineage-specific deletions or overexpression of Del-1 or its receptor β3 integrin. In Aim 1, it is proposed that Del-1 promotes osteoblastic differentiation by acting via its RGD motif on β3 integrin in osteolineage progenitors. Aim 2 involves the elucidation of the mechanisms by which Del-1 regulates osteogenesis in vivo and, moreover, examines the consequences of aging-related Del-1 deficiency on bone regeneration. It is also proposed that impaired bone regeneration in old mice can be reversed by local administration of Del-1. On the basis that the regenerative defect of the aged PDL-MSC niche is reversible and regulated by the extrinsic microenvironment, the findings of this proposal may potentially pave the way to novel Del-1-based approaches to rejuvenate niche functionality and thus enhance periodontal bone regeneration in old age.

项目概要 老年人对牙周炎的易感性增加，牙周炎是一种常见的炎症性疾病，可导致 牙齿支持组织（牙周组织）的破坏。这种敏感性增加可能是由于 牙周组织的免疫炎症状态和/或再生潜力的改变。受损 组织再生可能可以追溯到与年龄相关的间充质干细胞（MSC）生态位的改变 牙周膜（PDL），含有骨祖细胞。 Del-1 是一种体内平衡蛋白，由 独特的组织驻留细胞：它调节中性粒细胞（内皮细胞衍生的 Del-1）的募集和 凋亡中性粒细胞（巨噬细胞衍生的 Del-1）的胞吞作用，因此 Del-1 控制着凋亡的起始和 炎症的消退。其他研究表明 Del-1 在 PDL 中产生并促进 成骨细胞分化以及在牙槽骨消退过程中诱导新牙槽骨的形成 实验性牙周炎。然而，Del-1 表达在老年时严重减少。本项目调查 总体假设是，与衰老相关的 Del-1 缺陷可能导致 骨生成，从而导致老年牙周骨再生缺陷。该提案包括 两个具体目标并侧重于相关的基于动物模型的机制和干预研究，包括 具有谱系特异性缺失或 Del-1 或其受体 β3 整合素过度表达的小鼠。在目标 1 中，建议 Del-1 通过其 RGD 基序作用于骨谱系中的 β3 整合素来促进成骨细胞分化 祖先。目标 2 涉及阐明 Del-1 调节体内成骨的机制 此外，还研究了与衰老相关的 Del-1 缺乏对骨再生的影响。这也是 提出通过局部施用 Del-1 可以逆转老年小鼠受损的骨再生。上 认为衰老的 PDL-MSC 生态位的再生缺陷是可逆的，并受到外在因素的调节 微环境中，该提案的研究结果可能为基于 Del-1 的新型方法铺平道路 恢复生态位功能，从而增强老年牙周骨再生。