Potentials of Epigenetic Molecules in Attenuating the Phenotypes of Periodontitis

点击翻译按钮获取中文摘要

Periodontal disease represents one of the most prevalent diseases in adult population as 47% of Americans over age 30 have the disease. Periodontitis is a complex immune and inflammatory disease, characterized by three major pathological features: exacerbating inflammatory response, excess osteoclastic alveolar bone resorption and decreased osteoblastic bone formation. Unfortunately, there are only palliative treatments in clinics currently. Our laboratory has explored a variety of strategies to ameliorate the severity of the disease including application of bone marrow stromal cells (BMSCs) and induced pluripotent stem cells (iPSCs) with major transcription factors, such as Runx2, Osx and SATB2 in cell-based gene-therapy, but at the meantime experienced drawbacks and limitations of these approaches. Therefore, we are actively searching for a new therapy that blocks the major pathogenetic elements and stimulates endogenous factors to regenerate the tissues lost in periodontitis. Epigenetic molecules have recently emerged as potent regulators of gene expression and therapeutic agents for a variety of human diseases. We for the first time found that the novel synthetic BET protein inhibitor, JQ1, specifically inhibits periodontal inflammation and significantly reduces alveolar bone loss in murine periodontitis model. Additionally, we are the first to identify miR-335-5p and characterized its role in promoting bone formation and regeneration. Overexpressing miR-335-5p ameliorates tissue damage in experimental periodontitis which further provides a foundation and a strong premise for the current proposal. In this proposal we will use an elegantly designed and precisely synthesized nanoparticle (NP) system that will carry both JQ1 and miR-335-5p and specifically release them into major target cells in periodontitis, resulting in a block of the pathogenesis and activation of endogenous regenerative factors. In Aim 1, we will delineate the molecular mechanisms of miR-335-5p effects in periodontitis under gene deficient and overexpressing conditions using our newly generated genetically manipulated rodents. In Aim 2, we will define the epigenetic effects of nanoparticle-mediated precision and specific delivery of JQ1 and miR-335-5p on their corresponding target cells. In Aim 3, we will determine the therapeutic efficacy of combined application of epi-modulators in a mouse model of periodontitis. We will deliver the epi- biological nano-products simultaneously, individually, or alternatingly to assess the therapeutic impact at different disease stages. Outcome measures will include unbiased single cell RNA-sequencing, 16S rDNA profiling, qualitative and quantitative periodontal analyses and pharmacokinetics. Using innovative epigenetic approaches to understand the pathophysiology of periodontal disease and its therapeutic potentials is a paradigm shift. This investigation will be conducted by an interdisciplinary team composed of the PI and three C-Is who have profound knowledge and complementary skills in the following areas: Experimental Pathology and Bone Biology; Cell and Molecular Biology; Inflammation and Immunology, and Biomaterials and Drug Delivery.