Del-1: Molecular and Cellular Targets in Periodontitis

描述（由申请人提供）：牙周炎是一种炎症性疾病，可导致牙齿支持组织的破坏，并可能对全身健康产生不利影响。稳态机制的适当功能对于防止不必要的炎性组织损伤是必不可少的。内皮细胞分泌的蛋白质Del1（由EDIL 3基因编码）在体内起稳态作用，以调节牙周组织中的中性粒细胞迁移和局部炎症。然而，Del1表达在老年或某些炎症刺激中减少。初步研究还表明，Del1还表达并调节破骨细胞。因此，Del1可能作为炎症的看门人，并可能具有重要的治疗意义。本申请的总体目标是理解如何在分子信号传导水平上调节Del 1表达，定义新的Del 1功能，并鉴定Del 1多肽内的关键功能位点，其可以被利用作为 消炎药所提出的方法基于小鼠（野生型和Del 1缺陷型）和非人灵长类动物的体外和体内实验系统，以及用于轮回、破骨细胞生成和Del 1调节的体外人体试验。该提议的总体假设是，Del1是一种功能多样的分子，其稳态作用以调节导致炎性骨丢失的关键上游和下游事件，因此具有治疗牙周炎的治疗潜力。提出了四个具体目标。目的1探讨Del1在破骨细胞分化和功能中的作用及其机制。目的二是研究Del1基因表达调控的信号通路。目的3涉及Del1调控中性粒细胞迁移或破骨细胞生成所必需的结构域的功能定位。目的4将确定在非人灵长类动物的实验性牙周炎中用Del 1（或其结构域）局部治疗的功效。本项目的长期目标是建立Del 1（或Del 1衍生片段）作为人类牙周炎的有效治疗方法。由于Del1的保护作用被怀疑在其他炎症条件下，这一建议可能有超出牙周炎治疗的影响。重要的是，由于Del 1是内源性分子，其表达在炎性疾病中减少，因此在炎性病症中局部施用重组Del 1（或其片段）不太可能涉及安全性问题，而是应该恢复组织稳态。

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.