Beyond the classic function of bone, bone cells have been shown to regulate whole energy metabolism through bone-derived factors (osteokines). However, much of the research done to elucidate the pathophysiology of metabolic dysfuntion uses the classical approach of studying organs obviously implicated in energy metabolism. When Looking at the importance of skeletal integrity through the lens of evolution, we find that bone served a survival function. Humans had to consistently be mobile to look for food and shelter. Furthering this logic reveals that bone and energy metabolism are entwined. Therefore, this project aims to 1. identify bone factors that are associated with metabolic conditions and 2. to bridge our knowledge of the skeletal system represented by its cell types and our understanding of energy metabolism of the organism into one integrated subject.

Our research project offers a transformative advantage over conventional approaches by thinking with the end in mind (i.e translational potential) . We employ a multi-omics approach that goes beyond the conventional focus on single layers of biological information that will deepen our understanding of metbaolic diseases and accelerates identifying novel biomarkers and therapeutic targets.

• Interdisciplinary approach
• Multi-omics integration
• Translatioal potential

Our research offers potential for early diagnostics, novel biomarkers, and personalized therapeutic approaches for conditions like diabetes, osteoporosis, and diabetic osteoporosis. Our work fosters interdisciplinary collaboration and inspires future translational research and RnD with industrial partners.
This work promotes public awareness of the importance of bone health and ultimately aims to deliver tangible societal benefits.

• HIV infection is one of most serious concern in infectious diseases. We will perform anti-HIV assays for unmet medical needs in control of HIV infections with established novel assays. We have developed reverse transcriptase inhibitor that has novel mechanism of inhibition, translocation-inhibition (J Biol Chem, 2009). Dr Kodama participated in the primary screening and development of a new HIV integrase inhibitor, elvitegravir (J Virol 2009), and a unique reverse transcriptase inhibitor, islatravir, which phase III clinical trials by the Merck & Co., Inc. will complete, soon. We have a representative resistant HIV strain-library for anti-HIV screening and several target oriented high through-put screening systems.

We can establish high through-put screening for new targets, so please consult with us individually. We are open to joint development requiring BSL3/P3 experimental facilities and academic guidance including other microorganisms.

• Using the infectious SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2), we are evaluating and developing new therapeutic drug candidates as well as evaluating disinfectants. Further analyses such as mechanism of action and resistance may be applicable. Other pathogens, including influenza virus and drug-resistant bacteria, will be examined upon request and discussion. Through joint and collaborative research with domestic and overseas pharmaceutical companies and related companies, we have experience of their clinical application including basic research.

We support development and evaluation of various inhibitors and disinfectants for variants of SARS-CoV-2 as well as wild type.

• Using the yeast transcriptional activator Gal4 system, we reconstituted the production of amyloid beta (Aβ), responsible for Alzheimer disease. Aβ production could be monitored by the positive growth in the selection media or by the reporter enzyme (β-Gal). Utilizing familial Alzheimer disease mutants, we established a system to screen for mutations and chemicals that modulate gamma secretase activity and reduce toxic Aβ42.

Our yeast system can be used to screen for chemicals, natural products, food ingredients, genes, and mutations that modulate γ-secretase activity and block Aβ42 production specifically. We hope to conduct collaboration research with a willing company for a practical application of this technology in industry.

• The artificial control of gene expression by synthetic oligodeoxynucleotides (ODNs) has been the subject of considerable interest. In particular, ODNs conjugated with a cross-linking agent have been expected to enhance the inhibitory effect. Recently, microRNAs (miRNA) endogenously expressed small regulatory non-coding RNAs, are recognized as playing a critical role in regulating gene expression and the great concerns have been raised about efficient antisense oligonucleotides against miRNAs. We have already demonstrated that ODNs bearing a 2-amino-6-vinylpurine (2-AVP) derivative exhibited efficient interstrand cross-linking to cytosine selectively. The unique structural features of AVP are to possess both the hydrogen bond donor-acceptor sites as recognition sites and the vinyl group as a reactive moiety in a single molecule. Recently, we have developed of the novel cross-linking agents, which are designed based on the unique structure of AVP. These derivatives can react to thymine at the complementary site with highly selective and efficient under neutral conditions. We hope to conduct collaborative research with a willing company for a practical application of this technology in industry.

• Diabetes induces several complications, including retinopathy and nephropathy. In patients with type 1 diabetes as well as those with type 2 diabetes, pancreatic beta cells have reportedly decreased. Therefore, regeneration therapy of pancreatic beta cells may be very effective for major populations of diabetic patients. We discovered a neuronal network, from the liver, which selectively elicits pancreatic beta cell proliferation (Science 2008, Fig.). In a murine model with insulin-deficient diabetes, stimulation of this network improved diabetes. Thus, building devices which regulate the inter-organ neuronal network may lead to “regenerative therapy” for diabetes which regenerates pancreatic beta cells in the pancreas using patients’ own cells and patients’ own systems. We hope to conduct collaborative research with a willing company for a practical application of this technology.

• Obesity induced the metabolic syndrome, which causes cardiovascular diseases. Obesity has now become a major health concern not only in developed countries but developing countries. However, diet and exercise are still major therapies. We discovered endogenous systems maintaining homeostasis of energy metabolism and revealed several neuronal networks among organs to be responsible for the regulation systems.
• 1) Afferent neuronal signals from adipose tissue regulate appetite and prevent over-eating during obesity development (Cell Metab 2006)
• 2) Neuronal network from the liver enhances basal metabolic rates to prevent obesity development when energy store is increasing (Science 2006) 3) Neuronal network from the liver suppresses adaptive thermogenesis in brown adipose tissue (Cell Metab 2012).

On the basis of these original discoveries, we are aiming at developing new drugs and/or building devices which regulate the inter-organ neuronal networks and hope to conduct collaborative research with a willing company for a practical application to obesity therapy.