• 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.

• Marfan’s syndrome (MF) is a severe, systemic disorder of connective tissue formation. A variety of MFS therapies have been developed, including surgical therapy for aortic root aneurysm and dissection (AAD) that are life-threatening, traditional medical therapies such as β-adrenergic receptor or angiotensin II receptor blockers for slow aortic growth and to decrease the risk of AAD. However these treatments did not prevent tissue destruction in the AAD of MF. To develop preventive strategy for AAD, it will be necessary to identify molecular mechanisms of microfibril formation and an appropriate fibrillin-1 microfibril associated molecule. Recently, ADAMTSL6β, which is a microfibril-associated extracellular matrix protein contributes the regeneration of microfibril by promoting fibrillin-microfibril assembly. We try to develop ADAMTSL6β as a preventive medicine for AAD of MF by regeneration of fibrillin-1 microfibril assembly.

• 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.

• Breast cancer is one of the most common malignancies in women worldwide. Therefore, it is very important to investigate biological features of breast carcinoma in order to improve clinical outcome of the patients. It is well known that estrogens play important roles in the development of human breast carcinomas, and endocrine therapies are frequently used in these patients to block the intratumoral estrogen actions. In the Division of Pathology and Histotechnology, we analyze hormone actions in breast carcinoma by pathological methods as well as various molecular biological techniques.

It will be possible to newly develop diagnostic techniques regarding prediction of prognosis and/or effectiveness of treatment in breast cancer patients.

• Eleven strains of recombinant inbred (RI) mice derived from MRL/lpr and C3H/lpr mice were established. This RI is the only one in the world that randomly develops lesions such as nephritis, arthritis, sialadenitis, vasculitis, and production of autoantibodies in each strain. The genomes of the two strains of mice are randomly held in homozygous condition, and the phenotypes of each strain and the effects of administered drugs could be compared based on their genotype maps. It is possible to identify the regions of gene loci involved in the phenotype and drug sensitivity.

Development of diagnostic and therapeutic agents for autoimmune diseases. It can be applied to the elucidation of the mechanism of onset of immunological adverse events caused by immune checkpoint inhibitors and the development of drugs to prevent the onset of such events, and industry-academia collaboration with pharmaceutical companies, test reagent companies, etc. is possible.

• McH/lpr-RA1 mice are recombinant congenic mice descended from MRL/lpr and C3H/lpr mice and develop arthritis, vasculitis, and sialadenitis with high frequency and severity, with severe pannus formation similar to rheumatoid arthritis, polyarteritis nodosa, and Sjogren's syndrome. On the other hand, McH/lpr-RA1 mice do not develop systemic lymphadenopathy and severe nephritis as seen in MRL/lpr mice, so they are easy to breed and maintain and can be used for long-term drug administration experiments.

Development of diagnostic and therapeutic agents for collagen diseases. It can be applied to the elucidation of the mechanism of onset of immunological adverse events caused by immune checkpoint inhibitors and the development of drugs to prevent the onset of such events, etc. Industry-academia collaboration with pharmaceutical companies, test reagent companies, etc. is possible.

• 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.

• Focusing our reseach interest mostly on the recognition and complexation behavior control of bioplymrs, such as DNA/RNA, proteines and so on. Another topics are reaction control based on molecular recognition phenomena in both ground and electronically excited states, we are pursuing mechanistic and synthetic studies on asymmetric photochemistry with supramolecular biopolymers as chiral reaction fields.

• The development of organic molecules which function as a catalyst has been extensively investigated to achieve selective and efficient transformation of organic molecules. Brønsted acids and bases are commonly employed as the catalyst in synthetic organic chemistry. To aim at their functionalization, axially chiral phosphoric acids and axially chiral guanidine bases have been developed as chiral Brønsted acid and base catalysts, respectively. A variety of optically active compounds has been synthesized through the development of highly stereoselective reactions using these catalysts.

The development of chiral Brønsted acid and base catalysts has been accomplished as recoverable and reusable organocatalysts and highly stereoselective molecular transformations have been established using these catalysts. The present methodology is applicable to process chemistry in preparing medicines and relevant compounds on the basis of the selective and efficient molecular transformations thus developed with reduction of the waste material.

• Complexity of the cardiac contraction sequence is still not fully understood because the dynamic mechanical excitation process, which directly correlates with contraction, cannot be accurately measured by CT, MRI, SPECT, or conventional ultrasound. By developing a noninvasive novel imaging modality with high temporal and spatial resolutions (US patent 5840028), we have detected the minute mechanical response (velocity component) to the propagation of the action potential in the human heart or to detect the propagation of the vibrations along the heart wall caused by the valve closure (Fig. 2).
• By applying the same procedure to the human arteries, the regional change in wall thickness caused during one cardiac cycle can be measured with high spatial resolution (Fig. 1). From the measurement, the regional elasticity of tissue surrounding atherosclerotic plaque can be determined. By comparing the pathological findings with the distribution of elasticity, elasticity of lipid and that of fibrous tissue were determined. Thus, each point inside the plaque is classified into lipid or fibrous tissue using transcutaneous ultrasound (Fig. 3).

This novel method offers potential as a diagnostic technique for detection of plaque vulnerability with high spatial resolution.
We are prepared to provide academic consultations to companies interested in our research.

• Eleven strains of recombinant inbred (RI) mice derived from MRL/lpr and C3H/lpr mice were established. This RI is the only one in the world that randomly develops lesions such as nephritis, arthritis, sialadenitis, vasculitis, and production of autoantibodies in each strain. The genomes of the two strains of mice are randomly held in homozygous condition, and the phenotypes of each strain and the effects of administered drugs could be compared based on their genotype maps. It is possible to identify the regions of gene loci involved in the phenotype and drug sensitivity.

Development of diagnostic and therapeutic agents for autoimmune diseases. It can be applied to the elucidation of the mechanism of onset of immunological adverse events caused by immune checkpoint inhibitors and the development of drugs to prevent the onset of such events, and industry-academia collaboration with pharmaceutical companies, test reagent companies, etc. is possible.