Principle Investigator	Mutsuhiro Takekawa Professor and the Chair of Office of Support for Platforms for Advanced Technologies and Research Resources, the Institute of Medical Science, the University of Tokyo
Keyword for Support Function	Technical Training Course for animal model, fostering young scientists, international exchange, construction of animal model, genetically modification, genome editing, pathological analysis, behavioral analysis, chemical sensitivity, optogenetics, multi-functional electrode, zebra fish, molecular targeting and profiling (phenotype, chemical library, functional genomics, bioinformatics)
Grant period	FY 2022 - 2027
URL	https://plaza.umin.ac.jp/model/

Support Categories

General Management Group

Technical Training Course for young scientists

We organize seminars and lectures about the cutting-edge research including the technical content, by researchers involved in the platform. We also call on all participants to make presentations (oral or poster) or discussions. Our main objectives are to facilitate the understanding of construction and analysis of the advanced animal model, to promote networking among young scientists, and to promote joint research.

Outcome Presentation Symposium

We aim to promote networking among researchers and joint researches by organizing the symposium, special lectures and workshops on the relevant research fields where researchers present their outcome of the research supported by the platform.

Group for Animal Model Construction

Support for Mouse Model Construction	We construct and provide genetically modified mice upon requests from researchers. We conduct homologous recombination and genome editing using ES cells and mice’s embryo to introduce gene knockout (conditional/conventional) and genetic modifications (insert, replace, and introduce a point mutation.)
Support for Rat Model Construction	We construct and provide genetically modified rats (knock-out, knock-in, BAC-Tg and others) with the genome editing technology. The advanced and valuable rat models are available, including animal model of disease having human genetic mutation, tissue-specific Cre driver and GFP reporter genes.
Support for Virus Vector Construction	We support the production of genetically modified animals using the virus-mediated gene transfer. We construct and provide various virus vectors upon requests from researchers.

Group for Pathologic Analysis

Pathologic analyses on eukaryotic animals, mainly rodents	We can cover all sorts of pathologic alternations of living models, not only neoplasia but also inflammatory conditions, neurodegenerative diseases, and aging. We can also support to analyze the iPS cell-derived animals.
Analysis on morphological changes of organs upon drug administration. (determination of the phenotypes of genetically engineered animals that affect the corresponding human diseases. )	Because all members cover the whole area of pathology, we are flexible enough to find your person in charge, providing a high possibility of determining the phenotypes of genetically engineered animals.
Pathologic analyses on cause of fetal death and formation of tumors	We are experienced with the analyses on embryological abnormality and tumor forming ability with the advanced regenerative medical technology and developmental engineering such as iPS cells. We can analyze the teratoid tumor and determine the fetus’s congenital anomaly and the cause of death.
Support and training for pathologic stain	We can stain the tissues with Hematoxylin and eosin, in addition to special staining, and immunostaining. We can deal with in situ hybridization and capture the image with electron microscopes.

Group for Physiological Analysis

Support for behavioral analysis	We analyze a comprehensive behavior of genetically modified mice or drug-administered mice. If we determine some phenotypes, we will conduct the additional behavioral experiment and additional in vivo Calcium imaging experiment. If you cannot prepare mice, we support maintaining the mice under SPF conditions, and breeding.
Support for pharmacological analysis	We examine the link between the genes and the susceptibility of the controlled substances through extracting and analyzing the genetic data of your interest, using clinical data of the conventional susceptibility test of the controlled substances, genome specimen, and the related database. Also we analyze the genetically modified animals, and provide the biological specimen.
Support for operation analysis using the optical technology	We operate the multidimensional optical signal to collect data of the cell function. We develop and provide reagents used for light signal detection methods GECI including red, yellow, green, and blue calcium indicator XCaMPs.) as well as used in optogenetical operating method (ChR2 etc.). We support anything other than above related to optical technology.
Support for analyzing the obtained data using multi-functional electrodes	Our technical and analytical support activities in neurophysiology research are stated below. 1. Multi-point electrode for recording multiple neuronal activities 2. Carbon organic microelectrodes that are flexible, biocompatible, and can be used under MRI recordings 3. Virtual reality for small animals 4. Ultra-fine fluorescence endoscope for deep brain imaging 5. Activity-dependent manganese contrast-enhanced MRI 6. Support for analysis methods of the above data

Group for Molecular Profiling

Molecular profiling based on growth inhibitory profile across the JFCR39 cell line panel	We will estimate the potential biological activitity of a test compound by measuring the half growth inhibition concentration in each of the JFCR39 cancer cell line panel cell lines and comparing the similarity of the compound's growth inhibitory profile across the JFCR39 with those of reference compound. As a higher-level analysis, we will perform time-lapse analysis of its phenotypic effects by using high-content imaging system.
Molecular profiling based on cell morphology and phenotypic screening system	The aim of this cell morphology and phenotypic screening system is to evaluate the activity of the test compound against epithelial-mesenchymal transition (EMT) regulation, autophagy regulation, wound healing inhibition, or neuroprotection. Since these assay systems can evaluate the activity of the test compound in cytotoxicity-independent manner, they are also useful for the compounds that do not show any positive effects using cell line panel.
Molecular profiling based on transcriptome analysis	We will perform the transcriptome analysis of the cells treated with the test compounds and obtain the gene expression signatures. Then, we will compare the signatures of the test compounds with those available in various gene expression database. Through these analyses, we will provide information that is useful for prediction of the intracellular target molecular pathways of the test compounds.
Molecular profiling based on proteomic analysis	Cells are treated with the test compounds and proteomic analysis of lysates of the cells is performed by 2D-DIGE. Comparing the proteomic changes with that of standard compounds in our database, the target of the compounds will be estimated. Using quantitative data, the similarity between the compounds and standard compounds in the database are calculated by multivariate analysis. The target of the compound is estimated from the similarity. In addition, significantly changed protein spots caused by the compound is applicable for the estimation of the pathway and the target of the compound. If necessary, quantitative proteomics by LC-MS / MS will be performed to analyze the details of the increase/decrease in protein expression or proteins related to the compound action will be identified.
Molecular Profiling based on first-in-mouse analysis	Experimental animals such as mice are extremely useful models for first examining the action of compounds in individuals. Test compounds are administered to laboratory mice (ICR, etc.) orally (po), intravenously (iv), intraperitoneally (ip), etc. by a route according to the purpose of analysis and the physical properties of the compounds. Changes in individual life or death, behavior, physical condition, body weight, etc. are followed up for 2 weeks. Then, the mice are dissected and checked for abnormalities and weight of organs.
Molecular Profiling based on zebrafish phenotype analysis	We evaluate regulatory activities of the test compound on developmental signaling pathways with phenotypic screenings in embryos of zebrafish, a vertebrate model organism. In addition, this system re-evaluates results of other in-cell evaluation systems in vivo, and functions as transition to the mammalian analyses.
Distribution of compound libraries	We systematically collect many small compound inhibitors and distribute them as SCADS inhibitor kits for every researcher who needs them. You can use SCADS inhibitors kits for the evaluation of compound screening systems, the analysis of intracellular signals, the comparison of target molecules in your interest with known target molecules, and so on. We also distrubute the compound libraries comprised of those deposited by the researchers throughout Japan.
Identification of miRNA target genes by RNA sequencing	microRNA (miRNA) is large group of small (~22 nucleotides), single-stranded non-coding RNA. miRNA is mainly associated with gene regulation at post-transcriptional level via modulating the stability and translation of mRNAs. miRNAs bind to Ago protein to form the RNA-induced silencing complex (RISC). miRNA recruits the RISC to target mRNA and mediates the gene silencing by either target mRNA degradation or translational repression. In this program, we support the identification of miRNA target genes by RNA sequencing coupled with AGO2-immunoprecipitation
Functional genomics support by shRNA screening	Genome-wide RNAi technology in mammalian cultured cells provides an opportunity to identify genes that are functionally relevant to the mode of action of a compound in an unbiased and comprehensive manner. We support researchers to elucidate the mode of action of compounds of their interest by serving a barcoded-shRNA library screen.
Evaluation of target protein(s) for the test compounds	Chemical biology approach is powerful way for the mode of action analysis of the bioactive compounds found by cell morphology and phenotypic screening systems. Aim of this evaluation is to screen and identify binding protein(s) of the test compounds by using the molecular probes that are designed and synthesized based on their structure-activity relationship (SAR) study.
Analysis of genome-wide protein-protein interactions using cell-free based protein array	In this support, we will perform the screening of interacting proteins on human protein arrays consisting of about 28,000 recombinants constructed on the basis of wheat cell-free protein synthesis system, or identify and analyze proteins that interact with proteins to be studied by the grantee using the focused arrays classified by function or family, such as transcription factors and protein kinases, and also look for interaction inhibitors.
Estimation of protein-protein interactions using Surface Plasmon Resonance	Surface Plasmon Resonance (SPR) is one of the most commonly used techniques to estimate protein-protein interactions (PPIs) . The advantage of SPR is able to measure the binding affinities and association/dissociation kinetics of complexes in real time, in a label-free environment, and using relatively small quantities of materials. In our support, we provide the data of binding affinities and association/dissociation kinetics for PPIs of proteins provided from researchers.
Bioinformatics support	Bioinformatics support will be provided as needed in each of the two pillars of molecular profiling support activities, “compound evaluation” and “molecular search.” Specifically, predictive analysis based on machine learning using the deep learning algorithm SHAP and biostatistical analysis such as multiple logistic regression analysis are performed.