Research	＞Masatsugu Hori	printout （104ｋ）→
	Main study contents in COE	Elucidation of the molecular system of cardiac muscle cells and promotion of new drug development and medicine-engineering cooperation
	Representative researcher	Masatsugu Hori (professor)
	Institution	Laboratory of Internal Medicine and Molecular Therapeutics, Department of Medical Biosignaling, Graduate School of Medicine
	Key words	Molecular cell biology, Organogenesis, Genetic engineering, Photoengineering, Cardiomyocyte engineering
		�T　Development and morphogenesis of the heart �U　Molecular mechanism of hypertrophy and cell death of cardiac muscle cells �V　Control of the molecular system using photons
	�T　Development and morphogenesis of the heart 　　Cardiac muscle cells develop from the lateral regions of the mesoderm in response to various differentiation and growth factors. Cardiac muscle cells then migrate toward the median region, form a tubular structure, and through repeated rotations and local fusions complete a mature heart consisting of 4 cavities and 4 valves. However, factors involved in this series of morphogenic processes have hardly been known. We have analyzed functions of various factors involved in heart development by suppressions using the RNAi method and over-expression using retroviruses in chick embryos. As a result, we discovered that a new type of Semaphorin molecule (Sema6D), known as an axon guidance factor, plays an important role in early morphogenesis of the heart. We are presently preparing Sema6D-defect mice for analysis of its role in mammals. In this COE, we will investigate the relation between congenital abnormalities of the heart and mutations of Sema6D. 　�U　Molecular mechanism of hypertrophy and cell death of cardiac muscle cells 　　Cardiac muscle cell hypertrophy occurs to adapt to stress in all heart diseases such as myocardial infarction, cardiomyopathy, valvular disease, and hypertension, corresponding to the pressure and volume loads. However, when excess stress persists for a long time, cell death of cardiac muscle cells occurs, and the heart expands, resulting in heart failure. In this study, we will clarify the molecular mechanism of hypertrophy and death of cardiac muscle cells, identify the target molecules for treatment of heart failure, and develop a novel therapy for heart failure. We have recently clarified that MAP kinases, particularly apoptosis signal-regulating kinase (ASK1) related to apoptosis, play an important role in hypertrophy and cell death of cardiac muscle cells because they are resistant in mice with knockout-induced heart failure. In this study, we will investigate whether ASK1 can be used as the target molecule in the treatment of heart failure by introducing a mutant gene that inhibits activity of the enzyme in the animal model of heart failure. In addition, we will identify substances involved in cell death of cardiac muscle cells present downstream of ASK1 using proteomics and genomics techniques, and cell-biologically investigate functions of the identified substances using genetically modified mice. Based on the above, we will develop new drugs targeting molecules including ASK1 that are involved in cell death of cardiac muscle cells and play an important role in development of heart failure, aiming at clinical application. 　�V　Control of the molecular system using photons 　　Short wavelength ultraviolet and visible lights easily causes irreversible molecular degradation what we could see when fluorescence microscopic examination. However, utilizing infrared light, has lower single photon energy, might reduce non-specific molecular degradation. We have investigated how to regulate molecular structure by the specific regulation of fragmentation and activation of bio-molecules such as proteins or peptides, using the specific infrared LASER beam which resonates with targeted chemical bonds. 　In this COE project, we will endeavor to utilize this pin-pointed infrared LASER irradiation technique for a substitution of enzyme mediated reaction, regulation of physiologic activity, and drug delivery system combined with techniques of peptide and protein medicine. Further investigations of LASER molecular handling technique would bring us to a new life science era of microscopic fabrication of cellular environment. Other study contents of Hori laboratory ■Elucidation of the development mechanism of tissue damage and organ failure and establishment of a diagnostic and therapeutic strategy ■Elucidation of the molecular mechanism of ischemic responses in the heart and brain and study of the induction of an artificial ischemia-resistant response ■Large-scale study of the relationship between diabetes and arteriosclerosis ■Large-scale study and intervention study of the relationship between atrial fibrillation and arteriosclerosis ■Large-scale epidemiological survey and intervention study of myocardial infarction ■Analysis of genes related to diseases Hori associated page≫

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