Phytochemical Plant Molecular Science, Chiba University - Project

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The project is operated with three subgroups under the key words of ‘Diversity and Universality’. Three subgroups cooperatively drive the project by the strong leadership of the PI in a synergetic manner.

Subgroup 1: Functional genomics of plant metabolism

2.pngThis subgroup will deal with the genomics-related study, such as genomics, transcriptomics and metabolomics, of medicinal plants to reveal the genomics principle of production of useful plant metabolites. Genetic engineering and synthetic biology of the plant (specialized) metabolism are also within the scope.

Research platform for integrated functional genomics in plants
Technology platforms for integration of genomics, transcriptomics and metabolomics is constructed. This platform is applying to decipher the function of unknown genes not only from a model plant such as Arabidopsis but also from a variety of medicinal plants. The project is implemented with a strong bioinformatics activity.

Integrated genomic functional genomics of important medicinal plants such as licorice
Licorice is one of the most important medicinal plants widely used in Japanese-Sino traditional medicines Kampo. We will decode the whole genome sequence of a couple of licorice species. Then further investigation will be performed to identify the genes and genome regions responsible for the production of medicinal components in licorice. We will also extend the functional genomics study to other important medicinal plants.

Genome evolution and redesign of biosynthetic machineries of plant specialized metabolism
Plant specialized metabolism has been evolved under the selection pressure of natural environments. We will clarify the mechanism and theory behind the molecular evolution of plant specialized metabolism. In particular, we shall focus on the bioactive alkaloids and sulfur-containing metabolites. The mechanisms revealed will be directly applied to the efficient artificial biosynthesis of the useful compounds by using a cutting-edge technology such as genome editing.


Subgroup 2: Natural Product Chemistry

1.pngWe elucidate the “diversity and universality of phytochemicals and their biological functions” to contribute toward human health. In particular, we devote our efforts to the discovery of new natural products in plants, their chemical syntheses, evaluation of their biological activities, and expand the basic research results into development of medicines, reagents, and health-functional foods.

Identification of the active principles of medicinal plants, investigation of new biologically active natural products in medicinal plants, their chemical syntheses, and expansion to drug discovery research
Through the studies on investigation of biologically active natural molecules in medicinal plants, establishment of efficient synthetic route of these natural products, and medicinal chemistry research using our chemical libraries of natural and synthetic compounds, we aim at creation of drug candidates for treatment of cancer, dementia, pain, inflammatory bowel disease, etc., as well as at development of health-functional foods. A major part of our recent research orients to Rubiaceae, including the genera, Mitragyna, Uncaria, Psychotoria, and Ophiorrhiza. The leaves of a tropical plant, Mitragyna speciosa Korth., have been traditionally used as a substitute for opium. By phytochemical studies on the constituents of the plant, we have isolated 7-hydroxymitragynine, a minor constituent of this plant, which was found to exhibit potent opioid agonistic properties in vitro and in vivo experiments. Some synthetic derivatives of 7-hydroxymitragynine were found to possess potent and useful antinociceptive activity in mice. Using these compounds we aim at creation of ideal analgesics. To develop the lead-molecules effective to Alzheimer’s disease we search and synthesize the alkaloidal constituents in the plants belonging to Lycopodiaceae. In join research with group 1, we investigate the constituents in Ophiorrhiza plants to elucidate the biosynthesis of anticancer natural product, camptothecin, as well as the diversity and universality of its biological functions.

Search for small molecules having effects on cancer development from phytochemical constituents and natural products-based compounds
During our studies on search for bioactive natural products, we are recently particularly interested in screening programs targeting signaling molecules related to cancer-related biological pathways such as TRAIL, Wnt, and hedgehog signalings from various plant natural resources as well as natural products-based synthetic compounds.
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) has emerged as a promising anticancer agent due to its ability to kill cancer cells selectively. Wnt signaling is implicated in numerous aspects of development, cell biology, and physiology, while Wnt signaling can lead to the formation of tumors and other diseases when aberrantly activated. The hedgehog (Hh) signaling pathway has been implicated not only in a variety of developmental processes in wide range of organisms, but also in the formation of tumors including pancreas, lung, and others. We have isolated a series of natural products and natural products-based synthetic compounds with various effects on TRAIL, Wnt, and hedgehog pathways and studied analysis of molecular mechanisms of these active compounds.

Search and development of small molecules based on natural products which accelerate regenerative process
Transplantation of stem cells derived from ES cells and iPS cells is a big pillar of regenerative medicine. Acceleration of proliferation and differentiation of stem cells after transplantation are very important. In this research, “compounds which accelerate reconstructive processing" will be created based on natural products. We focused on Wnt, Hh and Notch signaling and bHLH transcriptional factors that control stem cells. Using “Target Protein Oriented Natural Products Isolation (TPO-NAPI)” with the key protein beads of these signaling, natural products that bind to these proteins will be isolated from a natural products extracts library. Small molecules which are candidates for regenerative medicine will be create through evaluation of bioactivity and synthetic chemistry.

Subgroup 3: Environmental response of phytochemical production

2016-01-20 16.13.28.jpgStudy of Plant’s Response to Environment
Plants produce secondary metabolites to utilize them for the defense of one’s bodies against environmental stresses. Secondary metabolites are self-defense molecules for the plant, and alternatively have harmful and/or beneficial biological activities for some of animals. Humans use a lot of natural product-derived medicines that have been developed from the finding of bioactive secondary metabolites in medicinal plant. There are interactions among gene expresstion, biosynthesis, accumulation, and growth environment in order to regulate contents of natural products in plants. Few scientific knowledge about those interactions is evident, therefore, the aim of our research is to clarify the effect of environmental factors (light, H2O, CO2, temperature, nutrients, air, humidity, etc) upon plant metabolism (contents, gene expression, biosynthesis, accumulation, etc).

Plant Supply for Natural Medicines
Limited supply of a natural medicinal plant as source of bioactive compounds could make serious delay on the process of drug discovery. We investigate the most suitable environment for such a rare natural medicinal plant to be cultivated and to contain medicinal compounds in stable and high concentrations.