Reserches

 The qualitive and quantitive turnover of biological membranes is essential to regulate the functions and destinies of every cells. Membranes are composed of various types of lipids, and lipids are pooled in lipid droplets (LDs) as well as plasma membrane and organelle membranes in different form of metabolites. LDs consist of a phospholipid monolayer encasing a core of neutral lipids (triacylglycerols and cholesterol esters, in mammalian cells). LDs are usually formed from the ER membrane, where a series of enzymes synthesizing neutral lipids reside. LDs in the cytoplasm primarily serve as lipid reservoirs for energy production or membrane synthesis. LDs can also prevent lipotoxicity. LDs contact with other organelle membranes, and are involved in lipid synthesis, autophagic and proteasomal proteolysis/lipolysis, and lipoproteins synthesis, among others. LDs are also related in different diseases such as obesity, fatty liver, hepatitis C virus reproduction, hereditary spastic paraplegia, neuronal lipids storage disease, moya-moya disease, and lipodystrophy. Recently we are focusing on the biogenesis and functions of the nuclear LDs (nLDs). They can be formed in hepatic cells and others by distinct mechanisms. nLDs are related in phosphatidylcholine synthesis in hepatoma cell lines and observed in human hepatocytes derived from biopsies with various liver diseases. On the other hands, nLDs are involved in transcriptions of tumorigenic factors in glioma cell lines. Currently, we are resolving unknown functions of cLDs and nLDs as regulators for membrane lipids turnover, clearance of protein aggregations, gene transcriptions, and DNA damage repair.

 The synaptic wiring formed on the soma-dendrites of neurons provides the characteristic computation dependent upon neuronal type. The generation of the synaptic wiring of cerebellar Purkinje cell (PC), which is composed of two types of excitatory (parallel fibers (PFs) and a single climbing fiber (CF)) and inhibitory inputs (basket cell axons and stellate cell axons), is evaluated by the 3D-images reconstructed through the observation serial ultra-thin sections of PC soma-dendrites by EM after labeling by tracer combined with immunostaining. The synaptic wiring along the proximal dendrites has been established through the formation of surplus PF and CF synapses followed by elimination. The maintenance of the established synaptic wiring along PC is evaluated by 3D-restructed images after destruction of PFs, CF, or both PFs and CF. The damage of PFs allows the regeneration of PF synapses by survived PFs with the maintenance of the spine density along distal dendrites, leading to recovery of the proper synaptic wiring along PC soma-dendrites. On the other hand, denervation of CF is compensated by newly formation of PF synapses along proximal dendrites under homeostatic plasticity. These data disclose different mechanism in the generation and maintenance of synapse/spine between proximal and distal dendrites.

 Cell degeneration induced by several reasons may not necessarily be the result of cell death. Therefore, identifying alteration in organelle preceding cell death is very important. Now, we pay attention to mitochondrial degeneration under the several situations as a candidate of key regulator for cell degeneration. So far, we showed that mitochondria dysfunction preceded cell degeneration in neural or muscular cells.

 Dr David Barker, an epidemiological researcher in the UK, proposed the Developmental of Origins Health and Disease (DOHaD) theory, based on evidence that the nutritional environment, including the intrauterine and pre- and post-conceptional periods, is related to disease predisposition in adulthood.  In considering nutrition during the periconceptional period, our research has focused on folic acid, an essential vitamin for fetal development and growth. Folic acids one of the water-soluble vitamins recommended for consumption before and during pregnancy to prevent neural tube defects in the fetus. Recently, there has been concern about excessive intake of folic acids from dietary supplements. We are currently investigating the possibility that an excess of methyl group donors during organogenesis may affect fetal development and growth.

 ◆ Research Agenda:

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