Nearly 50% of American adults over age 30 have periodontal disease (PD). The basic pathology of PD is excessive alveolar bone resorption leading to tooth loss. Furthermore, PD can trigger general inflammation, adversely influencing cardiovascular, central nervous, reproductive and endocrine systems. Our laboratory has explored a variety of strategies for treating this disease and is still actively searching for a more effective and practical therapy with minimal side effects to cure the disease. Long noncoding RNAs (lncRNAs) are a family of non-protein-coding transcripts with the length longer than 200 nucleotides. LncRNAs participate in a wide repertoire of biological processes and play important roles in gene expression and posttranscriptional processes and are also implicated in the pathogenesis of many diseases. However, the functions of lncRNAs in dental diseases are just beginning to be uncovered. LncRNA ANRIL was the first shared genetic risk factor of atherosclerosis, PD, diabetes and cancers, thereby coined to APCD. Our laboratory has performed extensive preliminary studies including studies on lncRNA-APDC knockout mice. Our hypothesis is that lncR-APDC inhibits inflammation, osteoclastic bone resorption and promotes osteogenesis and alveolar bone regeneration through specific epigenetic pathways, by which efficiently targeting the pathophysiology of periodontitis.
Aim 1 will determine the functions of lncR-APDC in periodontitis via loss- and gain-of-function approaches. Next generation RNA-Seq will be performed to elucidate the expression patterns of the participating genes and cellular pathways altered by the lncRNA dysregulation.
Aim 2 will use state-of-the-art techniques to determine the cellular localization of lncR-APDC and decipher the mechanisms by characterizing the protein and RNA binding partners and chromosomal regions regulated by the lncR-APDC.
Aim 3 will test the therapeutic effects of lncR- APDC in periodontitis to determine lncR-APDC?s effect on inflammation, osteoclastic bone resorption and alveolar bone regeneration. The results will provide a paradigm shift and advance the research field vertically in three ways. Firstly, we have initially found that lncR-APDC could play a pivotal role in cell differentiation and proliferation in PD. However, how this lncRNA is involved in PD progression is virtually unknown. Therefore, the results will reveal a novel pathological mechanism of PD deterioration and progression. Secondly, we will decipher the pathways of lncR-APDC modulating gene clusters in different cells playing active roles in the periodontal microenvironment and their roles in the PD progression, which will lead to the discovery of novel therapeutic targets. Finally, we will examine the potential utility of our newly constructed adenovirus conjugated lncR-APDC, as a safe and effective therapeutic measure for PD in dental clinics. An interdisciplinary team of investigators with complementary and synergistic skills will conduct the studies (Jake Chen ? Experimental Oral Pathology and Bone Biology; Qisheng Tu ? Cell and Molecular Biology; Thomas Van Dyke ? Periodontology and RNA-Sequencing; Hans Johansson ? RNA Biology and lncRNA FISH).
This rigorous and translational study is to exploit a long noncoding RNA APDC (lncR-APDC) as a novel therapy for treating periodontitis, the leading cause of tooth loss. We will determine the biological functions of lncR-APDC in periodontitis via (1) gene knockout strategy; (2) next generation RNA-Seq; (3) state-of-the-art techniques to determine its cellular localization; (4) characterizing the protein and RNA binding partners and chromosomal configuration; (5) mouse periodontitis models to further test the therapeutic effects of lncR-APDC in treating periodontitis. The outcome of this study will provide a paradigm shift in our current understanding of the pathophysiology of periodontitis and advance this rapidly moving research field vertically and significantly.
