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.

项目摘要 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 破坏牙齿支持组织(牙周组织)。这种易感性的增加很可能是由 牙周组织免疫炎症状态和/或再生潜能的改变。受损的 组织再生可以追溯到与年龄相关的骨髓间充质干细胞(MSC)利基的改变 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 吞噬凋亡的中性粒细胞(巨噬细胞衍生的Del-1)，因此Del-1同时控制启动和 消退炎症。其他研究表明，Del-1在PDL中产生，并促进 成骨细胞分化和诱导新牙槽骨的形成 实验性牙周炎。然而，Del-1的表达在老年时会严重减弱。这个项目调查了 最重要的假设是，与衰老相关的Del-1缺乏可能导致了 成骨，从而导致老年牙周骨再生缺陷。这项建议包括 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Del-1或其受体β3整合素的谱系特异性缺失或过度表达的小鼠。在目标1中，建议 Del-1通过其RGD域作用于β3整合素促进成骨细胞分化 祖先。目的2阐明Del-1在体内调节成骨的机制 此外，还研究了与衰老相关的Del-1缺乏对骨骼再生的影响。它也是 提出局部应用Del-1可以逆转老年小鼠受损的骨再生。论 老年PDL-MSC龛再生缺陷可逆性及受外源性调节的基础 微环境，这一提议的发现可能为基于Del-1的新方法铺平道路 恢复雀巢功能，从而在老年时增强牙周骨再生。