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Principal Investigator: JAKE JINKUN CHEN
Organization: TUFTS UNIVERSITY BOSTON
Fiscal Year: 2024
Award: $628,007
Funding agency: National Institute of Dental and Craniofacial Research
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).
Terms: <3' Untranslated Regions><3'UTR><Age><American><Applications Grants><Assay><Award><Awards and Prizes><Binding><Bioassay><Biocompatible Materials><Biological><Biological Assay><Biology><Biomaterials><Biomechanics><Biomedical Engineering><Bisphosphonates><Bone Density><Bone Diseases><Bone Formation><Bone Mineral Density><Bone Regeneration><Bone Resorption><Bone callus><Bony Callus><CLG4B><Callus><Cell Body><Cells><Cellular biology><Collaborations><Crossbreeding><DNA Molecular Biology><Data><Disadvantaged><Disease><Disorder><Dose><Drug Delivery><Drug Delivery Systems><Drug Targeting><Drugs><Dysfunction><Elements><Epidemic><Equilibrium><Experimental Pathology><Femoral Fractures><Foundations><Fracture Healing><Fracture due to osteoporosis><Frequencies><Functional RNA><Functional disorder><GELB><Genes><Genetic Alteration><Genetic Change><Genetic Hybridization><Genetic Markers><Genetic defect><Grant><Grant Proposals><Hand><Immune Globulins><Immunoglobulins><Individual><Intervention><Intervention Strategies><Investigators><Laboratories><Lamellar Bone><Luciferase Immunologic><Luciferases><MMP9><MMP9 gene><Mature Bone><Medication><Metabolic><Mice><Mice Mammals><Micro RNA><MicroRNAs><Molecular><Molecular Biology><Molecular Interaction><Murine><Mus><Mutation><NIH><National Institutes of Health><New Jersey><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Oophorectomy><Osteoblasts><Osteoclastic Bone Loss><Osteoclasts><Osteogenesis><Osteoporosis><Osteoporosis with fracture><Osteoporotic fracture><Ovariectomy><PTH gene><Paper><Parathyrin><Parathyroid Hormone><Pathway interactions><Peer Review><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phenotype><Physiopathology><Probability><Process><Progress Reports><Property><Proteins><Publishing><R-Series Research Projects><R01 Mechanism><R01 Program><Reporter><Reporting><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Risk><Role><SERMs><Scientist><Selective Estrogen Receptor Modulators><Signal Pathway><Site><System><Technology><Therapeutic Effect><Time><Transgenic Mice><United States National Institutes of Health><Untranslated RNA><Woman><ages><balance><balance function><bio-engineered><bio-engineers><bioengineering><biologic><biological engineering><biological material><biomechanical><biphosphonate><bisphosphonate><bone><bone disorder><bone fracture healing><bone fracture repair><bone healing><bone metabolism><bone tissue formation><bone wound healing><cathepsin K><cathepsin O><cathepsin O2><cell biology><cell type><cost><diphosphonate><disease model><disorder model><drug/agent><experience><experiment><experimental research><experimental study><experiments><female gonadectomy><femur fracture><fracture repair><gain of function><gene biomarker><gene expression biomarker><gene manipulation><gene marker><gene null><gene signature biomarker><genetic biomarker><genetic manipulation><genetically manipulate><genetically perturb><genome mutation><hands><improved><innovate><innovation><innovative><interventional strategy><knockout gene><loss of function><member><men><miR therapy><miR-based therapeutic><miR-based therapy><miRNA><miRNA therapy><miRNA-based therapeutic><miRNA-based therapy><miRNAs><microRNA therapy><microRNA-based therapeutic><microRNA-based therapy><nano particle><nano-sized particle><nanoparticle><nanosized particle><noncoding><novel><null mutation><osseous wound healing><osteogenic><osteoporosis associated fracture><osteoporosis related fracture><osteoporosis with pathological fracture><osteoporotic bone><overexpress><overexpression><parathormone><pathophysiology><pathway><patient prognosis><pharmaceutical><regenerate bone><regenerative><side effect><skills><social role><therapeutic miRNA><therapeutic miRs><therapeutic microRNA><tissue wound><translational study><wound><wounding><wounds>