Role of platelets in periodontal bone remodeling.

血小板在牙周骨重塑中的作用。

• 批准号: 10087691
• 负责人: TOSHIHISA KAWAI
• 金额: $ 0.53万
• 依托单位: NOVA SOUTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10087691
• 关键词: Adhesions; Adult; Affect; Affinity; Antibiotics; Applications Grants; Atherosclerosis; Autologous; Bacteria; Binding; Biological Assay; Biological Markers; Blood Platelets; Bone Regeneration; Bone Tissue; Bone Transplantation; Bone necrosis; Bone remodeling; CD100 antigen; CD72 gene; Cell surface; Cells; Cellular Structures; Centers for Disease Control and Prevention (U.S.); Cleaved cell; Clinical; Communicable Diseases; Connective Tissue; Defect; Development; Disease; Enzyme-Linked Immunosorbent Assay; Enzymes; Epithelial; Epithelium; Generations; Gingiva; Growth Factor; Hemorrhage; Hemostatic function; Histocompatibility; Histocytochemistry; Immune; Impairment; In Vitro; Incidence; Infection; Inflammatory Response; Insulin-Like Growth Factor I; Jaw; Lesion; Leukocytes; Ligaments; Ligands; Ligature; Liquid substance; Lymphocyte; Lytic; Mediating; Membrane; Molecular; Monitor; Monoclonal Antibodies; Mus; Natural regeneration; Neurons; Oral; Osteoclasts; Osteogenesis; Outcome; Pathogenesis; Pathogenicity; Pattern; Periodontitis; Periodontium; Plasma; Platelet Activation; Platelet-Derived Growth Factor; Play; Population; Production; Regenerative response; Reporting; Rheumatoid Arthritis; Role; TLR2 gene; TLR4 gene; TNF gene; TNF-alpha converting enzyme; TNFSF11 gene; Tendon structure; Testing; Thrombin; Thrombosis; Tissues; Transforming Growth Factor beta; Transplantation; Vascular Endothelial Growth Factors; Vascular Endothelium; aged; alveolar bone; base; bisphosphonate; bone; bone growth factor; bone loss; chronic inflammatory disease; healing; immunopathology; improved; in vivo imaging; inflammatory bone resorption; insight; novel; novel strategies; osteoclastogenesis; osteogenic; pathogen; pathogenic bacteria; plexin; protective effect; receptor; recruit; regenerative; regenerative therapy; soft tissue; tissue regeneration

Abstract This R15 grant proposal aims to study the possible pathogenic roles of platelets in periodontitis. Periodontitis, an oral polymicrobial infectious disease, is characterized by host immune-inflammatory responses to periodontal bacteria, leading to the destruction of bone and connective tissues. While many varieties of immune cells and components were studied in periodontal immunopathology, only a few studies reported the elevated recruitment of activated platelets in periodontitis lesion. Although platelets activated by thrombin and/or LPS play key host-protective roles in infection-induced tissue damage by thrombosis and induction of tissue regeneration by production of variety of growth factors, including, VEGF, PDGF, TGF-b and IGF-1, the possible pathophysiological role of platelets in periodontitis is largely unknown. Recent studies reported that the activated platelets are associated with pathogenesis of Rheumatoid arthritis and atherosclerosis, instead of eliciting host protective effects. While platelet-enriched plasma (PRP) is effective in induction of “soft tissue regeneration” in periodontium, PRP therapy applied to the alveolar bone defect caused by periodontitis shows inconsistent results in induction of “new bone formation.” This phenomenon indicates that the presence of some unknown molecules in platelets inhibits bone regeneration induced by bone growth factors, such as, TGF-b and IGF-1. To this end, we have targeted recently identified anti-osteogenic molecule, Semaphorin 4D (Sema4D), a negative regulator of IGF-1-mediated osteoblastogenesis (OB-genesis). It was reported that activated platelets release functionally active soluble Sema4D (sSema4D) because of TACE (ADAM-17) mediated shedding of membrane bound form of Sema4D. It is theorized that, similar to TNF-a of which functional maturation requires TACE-mediated shedding from its membrane bound form, TACE-mediated shedding may play a key role in generation of functional sSema4D. In the proposed project, we hypothesized that Sema4D produced by platelets not only suppresses OB- genesis, but also promotes pathogenic osteoclastogenesis (OC-genesis). We further established a sub- hypothesis that pathogen associated molecular patterns (PAMPs), in particular LPS, produced by periodontal bacteria are engaged in promoting the generation of sSema4D from platelets. This study will 1) establish the pathophysiological role of platelets in the context of inflammatory bone resorption lesion of periodontitis, 2) elucidate the molecular mechanism that arrests platelet-mediated bone regeneration in periodontitis, and, based on insights gained from 1) and 2), 3) develop a new approach to improve the effects of platelet-mediated bone regenerative therapy applied to periodontitis. This proposal represents a potential paradigm shift in the development of novel regenerative therapies for periodontitis and other bone lytic diseases.

抽象的 该R15赠款提案旨在研究血小板在牙周炎中的可能致病作用。 牙周炎是一种口腔多发性疾病，其特征是宿主免疫炎症 对牙周细菌的反应，导致骨骼和连接组织的破坏。而很多 在牙周免疫病理学中研究了各种免疫细胞和成分，只有少数研究 报道了牙周炎病变中活化血小板的募集升高。虽然血小板被激活 凝血酶和/或LP在通过血栓形成和血栓形成引起的感染引起的组织损伤中扮演关键的宿主保护角色 通过生产各种生长因子的产生，包括VEGF，PDGF，TGF-B和TGF-B和 IGF-1，血小板在牙周炎中可能的病理生理作用是未知的。最近的研究 报道激活的血小板与类风湿关节炎的发病机理和 动脉粥样硬化，而不是引起托管保护作用。 富含血小板的血浆（PRP）是有效诱导“软组织再生” 牙周，PRP疗法应用于牙周炎引起的肺泡骨缺损，显示不一致 导致诱导“新骨形成”。这种现象表明某些未知的存在 血小板中的分子抑制骨生长因子诱导的骨再生，例如TGF-B和IGF-1。 为此，我们针对的是最近确定的抗肌生成分子Semaphorin 4D（Sema4d），A IGF-1介导的成骨细胞生成的阴性调节剂（OB-GENESES）。据报道活化的血小板 由于TACE（ADAM-17）介导的脱落，释放功能活性的实体SEMA4D（SSEMA4D） SEMA4D的膜结合形式。理论上，类似于tnf-a的功能成熟 TACE介导的膜结合形式的脱落，TACE介导的脱落可能在 功能性SSEMA4D的产生。 在拟议的项目中，我们假设血小板产生的SEMA4D不仅抑制了 创世记，但也促进致病骨质核层生成（OC生成）。我们进一步建立了一个子 假设病原体相关的分子模式（PAMP），特别是由牙周产生的LPS 细菌参与促进血小板的SSEMA4D产生。 这项研究将1）在炎症骨的背景下建立血小板的病理生理作用 牙周炎的分解病变，2）阐明了阻碍血小板介导的骨的分子机制 牙周炎的再生，并基于1）和2）的见解，3）开发一种新方法 改善用于牙周炎的血小板介导的骨再生疗法的作用。这个建议 代表了新型牙周炎再生疗法发展的潜在范式转移 其他骨裂解疾病。