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Principal Investigator: JAKE JINKUN CHEN
Organization: TUFTS UNIVERSITY BOSTON
Fiscal Year: 2022
Award: $621,496
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Patients with type 2 diabetes (T2D) have substantially higher incidence of bone disorders, including as
much as a 64% greater risk of fracture as compared to those without T2D. High blood glucose levels adversely
alter bone cell functions, causing decreased bone formation and delayed wound healing with poor quality
tissue repair. Therefore, diabetic bone disease (DBD) is a serious health concern for more than 40 million
people in the US and 370 million in the world currently afflicted with T2D. Current treatments for DBD include
anti-resorptive drugs, selective estrogen receptor modulators, and anabolic (bone-forming) drugs. However,
these drugs target either the bone-formation or bone-resorption pathway, not both. Moreover, these drugs have
little direct effect on diabetic hyperglycemia, a major root cause of T2D bone disorders. Furthermore, recent data
indicate some anti-diabetic drugs have side effects that actually increase fracture risk in T2D. Therefore,
developing a safe and effective method to prevent DBD and restore and regenerate lost bone tissue in diabetics
is critically important. Long noncoding RNAs (lncRNAs) are a family of non-protein-coding transcripts with length
longer than 200 nucleotides. Emerging evidence suggests that lncRNAs play important roles in gene expression
and are involved the pathogenesis of many human diseases. Currently, there are over 60 clinical trials using
lncRNAs as a remedy. Our laboratory has recently identified and initially characterized a specific lncRNA that
promotes osteogenesis and inhibits adipogenesis in diabetes. It can recruit KDM6B and KDM4B and influence
the histone methylation of relevant genes. Its deficiency causes bone abnormalities and retards bone
regeneration and delays wound healing in mouse models. This newly discovered lncRNA is therefore coined
“lncR-DBD”, suggesting its potential roles in targeting the pathophysiology of diabetic bone disease. We have
successfully generated a lncR-DBD gene knockout mouse line which will enable us to further dissect the
biological function of this new lncRNA. Aim 1 will determine the cellular localization of lncR-DBD and explore
the epigenetic pathways using the state-of-the-art approaches; Aim 2 will define the mechanisms and alterations
in bone phenotype in lncR-DBD knockout mice; Aim 3 will use a novel nanohydrogel delivery system to
investigate the therapeutic effects of lncR-DBD on bone wound repair and fracture healing in diabetic mice. The
outcome of our study will provide a paradigm shift in current understanding of the pathophysiology of DBD and
have a significant impact on the future treatment of this epidemic disease. Firstly, building on our preliminary
findings that lncR-DBD plays a pivotal role in bone metabolism, this project will further reveal novel epigenetic
mechanisms of DBD. Secondly, we will decipher the pathways of lncR-DBD modulating genes in the diabetic
microenvironment, which will lead to discovery of new therapeutic targets. Finally, we will deliver the lncR-DBD
mimics using a novel nanohydrogel system as a safe, effective means for lncRNA-based therapy. An
interdisciplinary team of investigators with complementary and synergistic skills will conduct the studies.
Terms: <Adult-Onset Diabetes Mellitus><Anti-diabetic Agents><Antidiabetic Agents><Antidiabetic Drugs><Binding Proteins><Biocompatible Materials><Biological Function><Biological Process><Biology><Biomaterials><Biomechanics><Bisphosphonates><Blood Glucose><Blood Sugar><Bone Diseases><Bone Formation><Bone Regeneration><Bone Resorption><Bone Tissue><Boston><Calcitonin><Calcitrin><Cell Body><Cell Function><Cell Process><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chondrocytes><Clinic><Clinical Trials><Code><Coding System><Coin><Complication><DNA Molecular Biology><Data><Defect><Development><Diabetes Mellitus><Diabetic mouse><Disease><Disorder><Dose><Drug Delivery><Drug Delivery Systems><Drug Targeting><Drugs><Dysfunction><Epidemic><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Experimental Pathology><Family><Foundations><Fracture Healing><Functional RNA><Functional disorder><Future><Gene Expression><Genes><Health><Hyperglycemia><Impaired tissue repair><Impaired wound healing><Incidence><Institutes><Investigators><KO mice><Ketosis-Resistant Diabetes Mellitus><Knock-out Mice><Knockout Mice><L-Lysine><Laboratories><Length><Ligand Binding Protein><Ligand Binding Protein Gene><Link><Lysine><Maturity-Onset Diabetes Mellitus><Medication><Methods><Mice><Mice Mammals><Molecular><Molecular Biology><Murine><Mus><NIDDM><Natural regeneration><New Jersey><Non-Coding><Non-Coding RNA><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nontranslated RNA><Nucleotides><Null Mouse><Osteoblasts><Osteoclastic Bone Loss><Osteoclasts><Osteogenesis><Outcome><PTH gene><Parathyrin><Parathyroid Hormone><Pathogenesis><Pathologic><Pathway interactions><Patients><Persons><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacology><Phenotype><Physiopathology><Plant Roots><Play><Process><Protein Binding><RNA><RNA Binding><RNA Gene Products><RNA bound><Regeneration><Research><Research Personnel><Researchers><Ribonucleic Acid><Role><SERMs><Selective Estrogen Receptor Modulators><Site><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Subcellular Process><System><T2 DM><T2D><T2DM><Techniques><Technology><Therapeutic><Therapeutic Effect><Thyrocalcitonin><Transcript><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Universities><Untranslated RNA><Wound Repair><abnormal tissue repair><adipogenesis><adult onset diabetes><anti-diabetic><anti-diabetic drugs><antidiabetic><base><biological material><biomechanical><biphosphonate><bisphosphonate><bone><bone cell><bone disorder><bone fracture healing><bone fracture repair><bone healing><bone metabolism><bone tissue formation><bone wound healing><bound protein><cell type><delayed wound healing><developmental><diabetes><diabetes mouse model><diabetic><diabetic bone disease><diphosphonate><drug/agent><fracture repair><fracture risk><gain of function><histone methylation><human disease><hyperglycemic><ketosis resistant diabetes><knockout gene><lipid biosynthesis><lipogenesis><loss of function><maturity onset diabetes><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><noncoding><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><osseous wound healing><osteogenic><parathormone><pathophysiology><pathway><prevent><preventing><recruit><regenerate><regenerate bone><root><side effect><skills><social role><therapeutic target><therapeutically effective><tissue repair><translational study><type 2 DM><type II DM><type two diabetes><wound healing><wound resolution>