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，牙周炎是一种普遍的炎症性疾病， 破坏牙齿支持组织（牙周组织）。这种增加的易感性可能是由 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），窝藏骨祖细胞。Del-1是一种稳态蛋白， 不同的组织驻留细胞：它调节中性粒细胞（内皮细胞衍生的Del-1）的募集， 凋亡中性粒细胞的巨噬细胞源性Del-1，因此Del-1控制细胞凋亡的起始和 炎症消退。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。该项目调查 总的假设是，与衰老相关的Del-1缺乏可能导致 骨生成，从而导致老年牙周骨再生缺陷。这项建议包括： 两个具体的目标，并侧重于相关的动物模型为基础的机制和干预研究，包括 Del-1或其受体β3整联蛋白谱系特异性缺失或过表达的小鼠。在目标1中，建议 Del-1通过其RGD基序作用于成骨细胞系中的β3整合素促进成骨细胞分化 祖先目的二是阐明Del-1在体内调控成骨的机制 此外，还研究了衰老相关的Del-1缺乏对骨再生的影响。也是 提出老年小鼠受损的骨再生可以通过局部施用Del-1逆转。上 老年PDL-MSC龛的再生缺陷是可逆的，并受外源性 微环境，这项建议的发现可能为新的基于Del-1的方法铺平道路 以恢复生态位功能，从而增强老年牙周骨再生。