Del-1: Molecular and Cellular Targets in Periodontitis

Del-1：牙周炎的分子和细胞靶点

• 批准号: 8974790
• 负责人: Georgios Hajishengallis
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974790
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Affect; Age; Aging; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Biological Assay; Biology; CCAAT-Enhancer-Binding Proteins; Cell Differentiation process; Cells; Chronic; Complement Factor B; Data; Development; Disease; Dissection; Endothelial Cells; Epidermal Growth Factor; Event; Gatekeeping; Genes; Genetic; Gingiva; Glycogen Synthase Kinase 3; Goals; Health; Homeostasis; Human; In Vitro; Inflammation; Inflammatory; Integrins; Interleukin-17; Lead; Ligands; Ligature; Maps; Mediating; Modeling; Molecular; Molecular Target; Neutrophil Infiltration; Nuclear; Osteoclasts; Pathway interactions; Periodontitis; Pharmaceutical Preparations; Play; Proteins; Publishing; Recombinants; Regulation; Resolution; Role; Safety; Series; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Stimulus; System; TRANCE protein; Testing; Therapeutic; Time; Tissues; Tooth Diseases; Tooth structure; Wild Type Mouse; base; bone; bone loss; cellular targeting; chromatin immunoprecipitation; chromosome 1 loss; conventional therapy; domain mapping; drug efficacy; in vivo; inflammatory bone loss; mouse model; mutant; neutrophil; nonhuman primate; novel; osteoclastogenesis; polypeptide; receptor upregulation

DESCRIPTION (provided by applicant): Periodontitis is an inflammatory disease that causes destruction of the tooth-supporting tissues and may adversely affect systemic health. The proper function of homeostatic mechanisms is essential for protection against unwarranted inflammatory tissue damage. The endothelial cell-secreted protein Del1 (encoded by the EDIL3 gene) acts homeostatically in vivo to regulate neutrophil transmigration and local inflammation in the periodontal tissue. However, Del1 expression is diminished in old age or by certain inflammatory stimuli. Preliminary studies also suggest that Del1 is additionally expressed by and regulates osteoclasts. Therefore, Del1 can potentially act as a gatekeeper of inflammation and may have important therapeutic implications. The overall objective of this application is to understand how Del1 expression is regulated at the molecular signaling level, define novel Del1 functions, and identify key functional sites within the Del1 polypeptide that could be exploited as anti-inflammatory drugs. The proposed approach is based on in vitro and in vivo experimental systems in mice (wild-type and Del1-deficient) and non-human primates and in vitro human assays for transmigration, osteoclastogenesis, and Del1 regulation. The overarching hypothesis of this proposal is that Del1 is a functionally versatile molecule which acts homeostatically to regulate critical upstream and downstream events that lead to inflammatory bone loss, and, therefore, has therapeutic potential for the treatment of periodontitis. Four Specific Aims are proposed. Aim 1 will determine the role and mechanism(s) of Del1 in the differentiation and function of osteoclasts. Aim 2 involves the dissection of signaling pathway(s) regulating Del1 expression. Aim 3 involves the functional mapping of domains of Del1 essential for regulating neutrophil transmigration or osteoclastogenesis. Aim 4 will determine the efficacy of local treatment with Del1 (or domains thereof) in experimental periodontitis in non-human primates. The long- term goal of this project is to establish Del1 (or Del1-derived segments) as an effective adjunctive treatment for human periodontitis. As the protective role of Del1 is suspected in additional inflammatory conditions, this proposal may have implications beyond the treatment of periodontitis. Importantly, since Del1 is an endogenous molecule the expression of which is diminished in inflammatory disorders, the local administration of recombinant Del1 (or segments thereof) in inflammatory conditions is unlikely to involve safety issues, but rather should restore tissue homeostasis.

描述(申请人提供)：牙周炎是一种炎症性疾病，会导致牙齿支持组织的破坏，并可能对全身健康造成不利影响。体内平衡机制的适当功能对于保护机体免受不必要的炎性组织损伤至关重要。内皮细胞分泌蛋白Del1(由EDIL3基因编码)在体内以稳态方式发挥作用，调节中性粒细胞在牙周组织中的迁移和局部炎症。然而，Del1的表达在老年或某些炎症刺激下会减弱。初步研究还表明，Del1由破骨细胞额外表达并调节。因此，Del1可以潜在地作为炎症的守门人，并可能具有重要的治疗意义。本申请的总体目标是了解Del1表达是如何在分子信号水平上调节的，定义新的Del1功能，并确定Del1多肽中可被利用的关键功能位点 消炎药。所提出的方法基于体外和体内实验系统，在小鼠(野生型和Del1缺陷)和非人类灵长类动物中，以及体外人类对移行、破骨细胞形成和Del1调节的检测。这一建议的主要假设是，Del1是一种功能多样的分子，它以稳态的方式调节导致炎症骨丢失的关键上游和下游事件，因此，具有治疗牙周炎的潜力。提出了四个具体目标。目的1确定Del1在破骨细胞分化和功能中的作用和机制(S)。目的2对调控Del1表达的信号通路(S)进行剖析。目的3涉及调控中性粒细胞迁移或破骨细胞生成所必需的Del1结构域的功能图谱。目的4将确定Del1(或其区域)局部治疗非人类灵长类动物实验性牙周炎的疗效。该项目的长期目标是建立Del1(或Del1衍生片段)作为人类牙周炎的有效辅助治疗。由于Del1在其他炎症条件下的保护作用被怀疑，这一建议可能具有超越牙周炎治疗的影响。重要的是，由于Del1是一种内源性分子，在炎症性疾病中表达减弱，在炎症条件下局部应用重组Del1(或其片段)不太可能涉及安全问题，而是应该恢复组织的动态平衡。