All rights reserved			Research Projects in our Laboratory 1. Remodeling of vascular system and its involvement in diseases progression    Adult mature vascutature with tissue-specific differentiation provides the optimal tissue microenvironment. Especially, in nervous system, the blood vessels form the barriers between blood and tissue parenchyma which are called 'blood-brain barrier (BBB)' and 'blood-retinal barrier (BRB)'. Vacular barrier function is indispensable for normal functioning of neurons and glias in nervous tissues. However, it is known that the well organized vasculature in nervous tissues is remodeled to lose the barrier function under various pathological situations, and the disruption of vascular barrier often plays the pivotal role in progression of diseases such as ischemic cerebral diseases, diabetic retinopathy, Alzheimer disease and so forth. In our laboratory, we have analysed the pathophysiology of intractable nervous diseases from the aspect of vascular remodeling, and tried to specify the molecules which could be the targets for establishment of new therapeutic strategies.     [Reference 1； Referenece 2； Reference 3] 2. Cellular response to tissue hypoxia and its involvement in disease progression    Multicellular organisms show adaptive reactions for their survival when they are exposed to an atmosphere with reduced oxygen concentration. These reactions include increase in respiratory volume, switch from aerobic to anaerobic metabolism, erythropoiesis and angiogenesis. For these reactions, cells must change the expression of several hypoxia-responsive molecules such as erythropoietin and vascular endothelial growth factor. Hypoxia responsible element (HRE) was delineated in the genes of hypoxia-responsive molecules as the sequence indispensable for their hypoxia-induced transcriptional activation, and hypoxia-inducible factor 1 (HIF-1) was identified as a transcriptional factor that binds to HRE and regulates the expression of various hypoxia-responsive molecules. Increasing evidence has revealed that HIF-1 is a key molecule regulating the cellular response to tissue hypoxia. HIF-1 is composed of two subunits, HIF-1α and HIF-1β, and HIF-1 activity depends mainly on the intracellular level of HIF-1α protein, which is regulated to be in inverse relation to the oxygen concentration by an oxygen-dependent enzyme, prolyl hydroxylase 2 (PHD2). Thus, cells respond to tissue hypoxia by sensing the oxygen concentration as the enzyme activity of PHD2, regulating the HIF-1 activity and consequently changing the expression of various hypoxia-responsive molecules. Cellular response controlled by hypoxia-HIF-1 cascade is also involved in pathological situations such as solid tumor growth, diabetic retinopathy and rheumatoid arthritis. Under these pathological situations, the activation of hypoxia-HIF-1 cascade often leads to the acceleration of disease progression.    Understanding an aspect of disease progression triggered by tissue hypoxia might provide a clue to new therapeutic strategies for intractable diseases. Until now, we have established the role of HIF-1 in hypoxia-induced pathological angiogenesis such as that in diabetic retinopathy, and clarified an aspect of molecular mechanisms underlying the ischemia-induced disruption of vascular barrier function in nervous tissues.     [Reference 1； Reference 2； Referenece 3； Referenece 4] 3. Establishment of new criteria for histological diagnosis of gliomas    Recent progress in genetic diagnosis has changed the role of histopathological diagnosis in clinical medicine. Pathologists often face the reality that clinicians rely on the genetic diagnosis rather than the histopathological diagnosis when they plan the therapeutic protocols for patients, This tendency is unfortunately prominent in the diagnosis of gliomas. In our laboratory, we have analysed the histological specimens of gliomas from multiple aspects including the stemness of tumor cells as well as the reprograming of non-neoplastic neural cells, in order to establish the new diagnostic criteria which could provide more valuable information about biological features such as malignancy, resistance against therapies and so forth.     [Reference 1]