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Aiming for clinical application of integrated omics technology using the test specimen biobank system as a research resource
Human specimens collected in the laboratory are analyzed in multiple dimensions using mass spectrometry and spatial omics to comprehensively capture the molecular profiles of individual organisms. This enables us to accurately identify minute in vivo changes related to disease characteristics and treatment efficacy, with the aim of realizing personalized medicine. Furthermore, long-term accumulation of biobank data will contribute to the discovery of biomakers essential for disease prevention and early diagnosis. Our laboratory is the closest to clinical practice and provides a research platform for co-creation open to all departments, aiming to rapidly return research results to clinical practice, improve patient health, and innovate disease management.
1. Elucidation of the thrombus formation mechanism and development of new antiplatelet drugs using humanaized VWF-GPIbα mice (Dr.Kanaji)
Arterial thrombus formation is caused by platelets forming aggregates due to integrin α IIbβ3 activation caused by the binding of blood adhesion molecule von Willebrand factor (VWF) to platelet membrane glycoprotein GPIbα. Therefore, inhibiting VWF-GPIbα interaction may lead to the development of effective antithrombotic drugs. However, since this interaction is essential for normal hemostasis, inhibiting VWF-GPIbα binding carries the risk of bleeding, and administration of antibodies targeting GPIbα causes thrombocytopenia, so drug discovery has not yet been achieved. We are exploring ways to suppress pathological thrombus formation while maintaining normal hemostasis by suppressing integrinαIIbβ3 activation caused by VWF-GPIbα binding without inhibiting this binding. Another reason why it is difficult to develop drugs targeting VWF-GPIbα is that it difficult to study in mouse models and requires investigation in large animals because the VWF-GPIbα interaction is species-specific. We generated a knockout mouse model in which the platelet-binding domain of VWF is humanized, and then crossed it with a humanized GPIbα mouse to generate a mouse model in which the VWF-GPIbα interaction is humanized.
It can also be mentioned that. Based on this mouse model, we have created mice in which platelets express various mutant GPIbα, and are analyzing the function of GPIbα in pathological thrombus formation. Based on the knowledge obtained here, we aim to develop safer and more effective antiplatelet drugs that prevent blood clot formation while maintaining platelet adhesion (primary hemostatic ability).
2. Data-driven research, biomaker discovery, and developement of clinical testing methods through a clinical omics approach (Dr.Setoyama)
Aiming at a comprehensive understanding of biomolecules, we are developing data-driven research through a clinical omics approach that combines analysis of metabolome, lipidome, and proteome with spatial transcriptome analysis using multiple state-of-the-art mass spectrometers (five in total hospital laboratories, we also aim to search for biomakers associated with developing research aimed at social implementation of "clinical testing methods for mental health".)
3. Elucidation of molecular mechanism of obesity resistance in human TFAM-high expressing mice and development of therapeutic agents for obesity (Dr.Fujii)
Obesity, a cause of cardiovascular death, currently has no fundamental cure other than weight loss. As remote work becomes more prevalent in today's society, there is a strong concern that obesity will increase due to changing lifestyles, and there is an urgent need to develop novel therapies that aim to fundamentally eliminate obesity. We found that transgenic mice overexpressing human TFAM (mitochondrialtranscription factor A ) (TgTg mice), which were originally established in our laboratory, showed a very strong anti-obesity effect in response to a high-fat diet, which was attributed to enhanced metabolism by maintaining the activity of brown adipose tissue. This was attributed to the enhanced metabolic activity of brown adipose tissue. In addition, transplantation of primary progenitor adipocytes derived from brown adipose tissue of TgTg mice into wild-type mice showed a similar anti-obesity effect. While brown adipose tissue decreases with aging, BMI increases in humans, and our laboratory has been working to clarify the "maintenance mechanism of non-tired brown adipose tissue" via mitochondrial function in TgTg mice in order to correct cellular and tissue aging. We are developing a new treatment method that does not rely solely on "lifestyle modification".
4. Creation of drug resistance countermeasures to prevent host genome evolution of drug-resistant bacteria （Dr.Aihara)
When drug-resistant bacteria are exposed to antimicrobial stress in the patient's body, the DNA sequences of bacterial chromosomes and mobile genetic factors may change, resulting in the generation and selection of bacteria with further enhanced drug resistance. Our research aims to elucidate the intra-host genome evolution process of drug-resistant bacteria by genome analysis, and to create new drug resistance countermeasures to suppress the evolution process.
5. Genetic analysis of thrombosis using next-generation sequencers (Dr.Ueda)
Venous thromboembolism is a multifactorial disease represented by deep vein thrombosis, etc. In Japan, congenital thrombogenic predisposition is known as deficiency of blood coagulation inhibitory factors such as protein S, protein C and antithrombin. The Department of Laboratory Medicine of Kyushu University Hospital has been conducting thrombogenic predisposition analysis for more than 20 years, and has investigated etiologic genetic analysis and constitutional predisposition for venous thromboembolism. Our laboratory aims to establish analytical methods that can be applied not only to thrombosis but also to various other diseases by conducting genetic analysis using next-generation sequencers that enable advanced and high-speed processing.
6. Development of innovative approaches for disease diagnosis using spatial omics
In recent years, omics technology has become increasingly important in the diagnosis and treatment of diseases. In particular, spatial omics in clinical practice is expected to make a significant contribution to the elucidation of disease mechanisms and understanding of treatment methods by spatially analyzing gene expression patterns in individual cells and microstructures in specimen tissues.
This project will utilize a single-cell spatial imaging analyzer and mass spectrometry platform to integrate proteomics, lipidomics, and metabolomics information from brain tumors and renal biopsy tissues, furthermore conduct analysis including spatial omics. Thereby analizing in detail the changes at the molecular level in the tissues concerned. This will allow us to propose new approaches for early diagnosis and effective treatment of diseases.
This project will also open up new frontiers in disease diagnosis and treatment through the innovative integration of omics technologies and the advancement of spatial analysis, and its results are expected to have a significant impact on medical advances in clinical practice.
Launch of Xenium Analyzer (10X Genomics) on April 26, 2024
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