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Second Department of Anatomy

Research room themes

In an organism, control systems of biological function, such as the immune, the endocrine, and the nervous systems, form a complex network to maintain their homeostasis; however, destruction of such networks causes various diseases. Research on each system has been conducted on their own and have made progresses. For example, past research in immunology focused solely on the immune system and had made significant advances. However, pathologies of autoimmune diseases and allergies are poorly understood, and not many therapies are available for these diseases. This is because pathologies of allergies and autoimmune diseases occur in the body and cannot be observed in vitro in the exact same way. Moreover, other than the immune system, the nervous and the endocrine systems are considered to be related to each other in a complicated way. 

In our research room, we make the most use of not only the morphological method, but also molecular biological, biochemical, immunological, and behavioral-physiological methods to conduct basic research to reveal the complex network of the control systems of biological function (such as the immune, the nervous, and the endocrine systems) ,with the main theme of cytokine. We aim to “reveal the pathologies caused by abnormal control of biological function induced by cytokines”. For this purpose, we focus in particular on the “pathologic network of food intake, obesity, and diabetes mellitus,” and “correlation between abnormalities in production or development of nervous system and diseases,” and currently analyze the pathology of molecular dysfunction in various knockout animals.

(1) Molecular mechanism of obesity and development of lifestyle-related diseases (Figure 1)

Due to a change from a traditional to western-type diet in recent years, the prevalence rate of metabolic syndrome in Japan is increasing yearly, and it is urgently needed to reveal the molecular bases of the syndrome and to develop therapeutic methods. Oncostatin M (OSM) is a cytokine belonging to the interleukin-6 (IL-6) family, and we conduct research on the association of metabolic syndrome with OSM. We analyzed OSMRβ, an OSM receptor subunit, in knockout mice and have revealed the inhibitory effects of OSM on the developments of obesity and diabetes mellitus (J Biol Chem 288: 21861-21875, 2013; J Biol Chem 289: 13821-13837, 2014). Additionally, we have revealed that OSM improves the obesity and diabetes mellitus in mice given a high-fat diet, which are model mice for metabolic syndrome, and ob/ob mice (Diabetologia 58: 1868-1876, 2015). On the basis of above-mentioned research findings, we currently analyze the detailed mechanism of OSM to improve metabolic syndrome;
at the same time, we conduct research aiming to develop a drug that acts on the OSM signaling pathway.

Figure 1: With a high-fat diet load, metabolic syndrome progressed more in OSMRβ knockout mice than in wild-type mice (Left). In addition, when OSM was given to mice with metabolic syndrome, symptoms including obesity, insulin resistance, and fatty liver were improved (Right).

(2) Molecular mechanism to control food intake

Leptin and ghrelin that are produced in the peripheral tissues act on the hypothalamus, the feeding center, to play an important role in regulating food intake and sugar metabolism. However, the mechanism has not been revealed completely. We isolated the new genes induced by leptin in the hypothalamus using a subtractive PCR method and have revealed that negative regulatory element-binding protein (NREBP), a transcriptional repressor, suppresses the development of ghrelin receptor (J Biol Chem 285: 37884-37894, 2010). Furthermore, we have identified the fasting-induced genes in the hypothalamus using a microarray and have revealed the significance of AFF4, which is a transcription factor, for the activation of AMPK signaling by ghrelin (J Biol Chem 287: 19985-19996, 2012). Presently, we analyze the function of the new genes induced by leptin and fasting.

(3) Functional analysis of gene cluster associated with production and formation of the nervous system

We perform functional analyses of TROY, kirrel3, and LRRN4, which are expressed in the nervous system during the fetal stage, using genetically modified animals. The kirrel3 gene is widely expressed in the central nervous and sensory systems (Neuroscience 133: 615-624, 2005; Neuroscience 150: 880-886, 2007). Possible association of kirrel3 gene abnormality with developmental problems, including autism and mental retardation, has been reported; however, its mechanism is unknown. We conduct research on the association of the kirrel3 gene abnormality with these developmental problems using kirrel3 knockout animals and perform pathological analysis of the mechanism. Furthermore, the LRRN4 gene is an essential molecule for memory retention in the central nervous system (Mol Cell Biol 25: 4166-4175, 2005). However, the LRRN4 gene was also highly expressed in the peripheral nervous system during the period of synaptogenesis of nerve cells specific to the spinal ganglion (Neurosci Lett 531: 24-29, 2012; Neurosci Lett 548: 73-78, 2013). Presently, we examine the function of the LRRN4 gene in the development and formation of the peripheral nervous and sensory systems.

(4) Clarification of pain and itch mechanisms and their application to therapy

As for the molecular mechanisms of development and maintenance of inflammatory pain and neuropathic pain, we conduct research with focuses on roles of macrophage/microglia and actions of cytokine/chemokine (Neuroreport 22: 911-917, 2011). In addition, we revealed that IL-31 receptor A (IL-31RA) and OSMRβ coexist in the same cell of the dorsal root ganglion neuron of mice (Neuroscience 142: 1263-1271, 2006). (Figure 2) We also examine the associations of OSM and IL-31 with intense itch,
in diseases such as atopic dermatitis.

Figure 2

Figure 2: Double immunostaining in a dorsal root ganglion neuron
A: Immunostaining image for IL-31RA (green)
B: Immunostaining image for OSMRβ (red)
C: Superimposed immunostaining image of A and B. Colocalization of green and red results in yellow color, and all IL-31RAs and OSMRβs coexist in some subset of small sized neurons. (Yato)