Research Project 「JP-PDF」

Investigating the molecular mechanism of HIF in hypoxic stress

The top three causes of death in Japan are malignant tumor, ischemic heart disease, and cerebral vascular disease. A common cause of these diseases is low oxygen tension in our body, known as hypoxic stress. The key transcription factors that regulate response to hypoxic stress are the Hypoxia Inducible Factors (HIFs). There are 3 types of HIFs: HIF-1α are expressed ubiquitously, HIF-2α are mainly expressed in endothelial cells, and HIF-3α works as an inhibitor against HIF-1α and HIF-2α.

In our laboratory, we investigate the molecular mechanisms of HIFs for hypoxic responses in vivo. We investigate the roles of HIF-2α for tumor vascularization, erythropoiesis, retinopathy of prematurity using HIF-2α knockdown mice. We also analyze the roles of HIF-3α for pulmonary hypertension and lung development using HIF-3α knockout mice. We try to clarify the diversity of HIF functions in response to various hypoxic stimuli.

Analysis of functional adult stem cells and progenitor cells for clinical application

Adult stem cells are undifferentiated cells, found in  adult tissues, which have stem cell characteristics such as self-renewal and differentiation potency. Since the use of embryonic stem cells is controversial, researchers are now investigating adult stem cells as a source of cells for application in regenerative medicine, the goal of which is to replace the dysfunctional cells in the tissue or support in the recovery of local cells. However, the self-renewal, proliferation, and other properties of the various adult stem cells are different so it is necessary to properly analyze their characteristics and their potency before applying adult stem cells in clinical treatment for specific disease.

In our laboratory, we are focusing on  the analysis of the biological characteristics and functions of mesenchymal stem cells and endothelial progenitor cells from several sources for application in future clinical treatments. Furthermore, we are aiming to clarify the underlying mechanisms regulating mesenchymal stem cells and endothelial progenitor cells in order to support tissue or organ recovery.

Researching the relationship between cancer and stem cells

To cure cancer, it is necessary to understand how cancer cells interact with local resident cells, including stem cells.

Our lab is researching how cancer cells 'communicate' with tissue stem cells using breast cancer cell lines and human tissue-derived messenchymal stem cells.

Retinal Regeneration Project

Glaucoma is a disease where the optic nerve (which connects the eyeball and the brain) is damaged and the vision is gradually lost. Once lost, our vision cannot be restored and may eventually lead to blindness. The number of glaucoma patients in the world has reached about 76 million, and it is projected to exceed 100 million by 2040. Retinal ganglion cells, which are damaged by glaucoma, are located in the innermost part of the retina and play an important role in forming optic nerve connection that transmit light information to the brain. Current glaucoma treatments are limited to lower intraocular pressure or neuroprotective therapy, which cannot recover the loss or damaged RGCs, therefore loss of vision cannot be recovered. Since it is not possible to recover, treatment using regenerative medicine technology is expected to be novel therapy. Through collaboration with Lab of Regenerative Medicine and Stem Cell Biology (Ohneda Lab), Department of Advanced Vision Sciences pursue the research of RGC regeneration. We are Associate Professor Shinichi Fukuda, Assistant Professor Toshiharu Yamashita, Donny Lukmanto (Postdoctoral Fellow), and Tran Thi Hang (HBP student). In recent years, direct reprogramming, which directly transforms cell differentiation without going through the stage of pluripotent stem cells, has attracted attention. In fish and birds, it is known that when the retina is damaged, Muller glia (type of retinal glia) cause reprogramming and differentiate into nerve cells in the retina. This pathway was thought to be blocked in mammals, but recently reported that it is directly reprogrammed in juvenile mice. Inspired by this fact, we aim to regenerate RGC through direct reprogramming approach. We conduct basic experiments every day so that this technology can be applied to the treatment of glaucoma in the near future.