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

基本信息

批准号：
10312010
负责人：
Georgios Hajishengallis
金额：
$ 33.08万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/10312010
关键词：
Address Affect Age Age-Months Aging Animal Model Apoptotic Area Back Biological Assay Biology of Aging Bone Regeneration Bone Tissue Cells Chronic Collaborations Defect Development Disease Elderly Endothelial Cells Endothelium Functional disorder Genetic Germany Homeostasis Human ITGB3 gene Immunity Impairment In Vitro Inflammation Inflammatory Integrins Intervention Studies Knock-out Lead Leukocytes Location MAPK3 gene Mesenchymal Mesenchymal Stem Cells Modeling Molecular Mus Neutrophil Infiltration Osteogenesis PTK2 gene Paper Pennsylvania Periodontal Diseases Periodontal Ligament Periodontitis Periodontium Predisposition Prevalence Proliferating Proteins Publications RGD (sequence)Regenerative capacity Research Resolution Role Severities Signal Transduction Source Testing Therapeutic Tissues Tooth structure Transgenic Organisms Universities Work age related aged alveolar bone base bone loss chromosome 1 loss experimental study human old age (65+)immunoregulation improved in vivo in vivo Model insight macrophage mutant neutrophil novel osteoblast differentiation osteogenic osteoprogenitor cell overexpression progenitor receptor recruit regeneration potential regenerative stem cell niche stem cell self renewal stem cells tissue regeneration tissue repair tool transcription factor

项目摘要

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.

项目摘要最古老的对牙周炎的敏感性增加，这是一种普遍的炎症性疾病破坏牙齿支持组织（牙周）。这种提高的敏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间充质干细胞（MSC）壁ni的年龄相关的改变牙周韧带（PDL），含有骨化剂。 Del-1是一种稳态蛋白，由不同的组织居民细胞：它调节中性粒细胞的募集（内皮细胞衍生的DEL-1）和凋亡嗜中性粒细胞（巨噬细胞衍生的DEL-1）的肿瘤细胞增多症，因此DEL-1控制着主动性和炎症的解决方案。其他研究表明，DEL-1是在PDL中产生的，并促进成骨细胞分化，并在分辨率下诱导新的肺泡骨的形成实验牙周炎。但是，DEL-1表达在老年时大大降低。该项目调查与衰老相关的DEL-1缺乏症可能导致失调的总体假设成骨，从而导致老年牙周骨再生缺陷。该提案包括两个具体的目的和侧重于相关的基于动物模型的机械和干预研究，包括具有特定谱系缺失的小鼠或DEL-1或其接收器β3整联蛋白的过表达。在AIM 1中，提出了 DEL-1通过在骨髓中的β3整合素上通过其RGD基序作用来促进成骨细胞分化祖先。 AIM 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缺乏对骨再生的后果。也是提出，旧小鼠的骨骼再生受损可以通过DEL-1的局部给药来逆转。在依据是，老化的PDL-MSC利基市场的再生缺陷是可逆的，并由外在的微环境，该提案的发现可能有可能为新颖的Del-1方法铺平道路恢复生态位功能，从而增强老年牙周骨再生。