Wednesday, May 8, 2024
5/8/2024
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
