This renewal grant application represents a deepened extension of the current grant (DE25681) focusing on the bone-enhancing effects of microRNA (miR)-335-5p, first identified and characterized in our laboratory. We have published over 9 peer-reviewed papers and won many prizes and awards in reporting the results. We have recently reported our new discovery of the function of miR-335-5p in inhibiting osteoclast differentiation and bone resorption. We further found that miR-335-5p exerts its inhibitory effect through its binding to the 3?UTR elements of igsf3 (immunoglobulin superfamily, member 3). Igsf3?s increased expression during the process of osteoclast differentiation is reversely correlated with the expression of miR-335-5p. This new discovery together with the well-characterized anabolic osteogenic effect of miR-335-5p, has led us to speculate that miR-335-5p is a potent pharmaceutical candidate for treating osteoporosis and its related bone disorders, where the balance between bone formation and resorption is disturbed. At present, osteoporosis treatments include anti-resorptive drugs and anabolic bone-forming drugs. However, these drugs target either the bone-resorption or bone-formation pathway, but not both. Many protein-based therapies have the disadvantages including side-effects and the high cost. We have generated both miR-335-5p gene knockout (loss-of-function) and overexpression (gain-of-function) mice. These two mouse lines will provide the most advanced and sophisticated approaches for gene manipulation to achieve our research purposes. Collaborating with scientists and bioengineers at the New Jersey Institute of Technology, we have developed novel and cutting-edge targeted nanoparticles for the first time to precisely deliver miR-335-5p to the target cells where it can exert its dual-effects in both bone-resorption and bone-formation pahways.
Aim 1. To explore the molecular mechanism of the newly discovered function of miR-335-5p in suppressing osteoclast activity and bone resorption;
Aim 2. To use our newly generated miR-335-5p gene knockout and overexpression mice to characterize the multilayered functions of miR-335-5p in bone metabolism;
Aim 3. To apply newly developed targeted nanoparticles to deliver miR-335-5p to specific cell types and determine its therapeutic effects on bone wound healing and reversal of osteoporosis. We will determine the therapeutic effects of miR-335-5p given effective concentration, optimal frequency, and accurate duration of administration to maximize its functions at both cellular and organismal levels. This renewal project is conceptually, technically, and interventionally innovative. The advantageous features of miRNA-based therapy will allow this translational study to shift the paradigm in understanding, treating and ultimately curing osteoporosis and its related bone disorders. An interdisciplinary team of investigators with complementary and synergistic skills will conduct the studies (Jake Chen ? experimental pathology and bone biology; Qisheng Tu ? cell and molecular biology; Xiaoyang Xu ? biomaterials and drug delivery).
This renewal grant application represents a deepened extension of the current grant (DE25681) focusing on the bone-enhancing effects of microRNA (miR)-335-5p, first identified and characterized in our laboratory. Our recent studies have demonstrated that miR-335-5p has important dual-effects: inhibiting osteoclastic bone resorption and promoting osteoblastic bone formation, therefore miR-335-5p is a potent pharmaceutic agent for treating osteoporosis and its related bone disorders, where the balance between resorption and formation is disturbed. Applying our recently generated miR-335-5p gene knockout and overexpressing transgenic mouse lines our newly developed, cutting-edge targeted nanoparticle system will be used for the first time to precisely deliver miR-335-5p to the distinct cell types to modulate both bone anabolic and metabolic pahways, which will allow this translational study to shift the paradigm in understanding, treating and ultimately curing osteoporosis and its related bone disorders.
|Jiang, Hua; Wu, Yuwei; Valverde, Paloma et al. (2018) Central adiponectin induces trabecular bone mass partly through epigenetic downregulation of cannabinoid receptor CB1. J Cell Physiol :|
|Sui, Lei; Wang, Ming; Han, Qianqian et al. (2018) A novel Lipidoid-MicroRNA formulation promotes calvarial bone regeneration. Biomaterials 177:88-97|
|Tang, Yin; Zhang, Lan; Tu, Tianchi et al. (2018) MicroRNA-99a is a novel regulator of KDM6B-mediated osteogenic differentiation of BMSCs. J Cell Mol Med 22:2162-2176|
|Zheng, Leilei; Tu, Qisheng; Meng, Shu et al. (2017) Runx2/DICER/miRNA Pathway in Regulating Osteogenesis. J Cell Physiol 232:182-91|
|Zhang, Lan; Tang, Yin; Zhu, Xiaofang et al. (2017) Overexpression of MiR-335-5p Promotes Bone Formation and Regeneration in Mice. J Bone Miner Res 32:2466-2475|
|Xuan, Dongying; Han, Qianqian; Tu, Qisheng et al. (2016) Epigenetic Modulation in Periodontitis: Interaction of Adiponectin and JMJD3-IRF4 Axis in Macrophages. J Cell Physiol 231:1090-6|