Project Outline
A paradigm shift from reactive to preventive health care
To ensure the sustainability of our rapidly aging society, it is crucial that we establish healthcare systems that firstly prevent chronic inflammatory conditions such as fibrosis, cancer and lifestyle diseases, and secondly, that allow early diagnosis and intervention when these diseases do occur. Conventionally, the focus of preventive medicine was to identify risk factors based on epidemiology, biochemistry and cell biology, and then to try and reduce the health risk. This approach identified many external environmental risk factors such as those in the natural environment, social environment, and workplace as well as internal risk factors, including those dependent on lifestyle habits. In some cases, this approach resulted in cures for disease.
In addition, while the epidemiological advances stemming from the human genome project have revealed the contribution of genetic factors such as point mutations to disease, they have also highlighted the large contribution of non-genetic internal and external environmental factors to many intractable diseases. These risk factors are variable rather than fixed, meaning that their effects are also preventable. However, because it is impossible to exclude all environmental risk factors from everyday life, the challenge for preventive medicine is to understand the biological mechanisms underlying disease and prioritize the risks accordingly. As a backup, preventive medicine also needs to establish methods for early diagnosis and intervention in disease.
Socio-cellular analysis of inflammation from the perspective of individual cells
When faced with internal and external stressors, biological defense mechanisms such as the immune and endocrine systems trigger an inflammatory response in line with the progression of chronic inflammatory disease. Through the prolongation or recurrence of inflammation, following the development of pre-disease tissue pathology that is accompanied by subjective symptoms, an abnormal adaptive state (inflammatory memory) becomes established in which cellular and tissue dysfunction is present. When this chronic inflammatory state persists, fibrosis and other impairment of tissue function becomes irreversible, leading to lifestyle diseases such as diabetes, cardiovascular disorders and chronic kidney disease.
When the development of these diseases is considered at level of individual organs, in addition to transformations in individual cells, changes occur in the interactions between different cell types (cells making up tissue structures and infiltrating immune cells), as well as in cellular activation states, hypoxia, metabolic responses, the extracellular matrix and networks of soluble factors. Biological tissues are maintained by interactions between a heterogeneous mix of cells each with varying purposes such as respiration and metabolism. These interactions can be likened to human society, which is composed of individuals of various gender, age, occupation and ability, and where connections between individuals are fluid but also follow a basic set of rules. In this project, we consider inflamed tissues to represent cellular societies of inflammation. By modeling the societal changes that accompany the progression of disease, we aim to prevent and regulate that process.
Comprehensive single-cell transcriptome analysis will enable socio-cellular analysis of inflammation
Traditional immunological and pathological approaches to inflammation research examined overall or averaged qualitative and quantitative changes in whole organs or cell samples consisting of hundreds to thousands of cells. As a result, it has been difficult to study the complex processes occurring in the pre-disease condition, in which changes occur in small, localized groups of cells that then influence surrounding cells, eventually resulting in changes to the cellular society. To overcome this limitation, in this project we will analyze inflamed tissues using microplate-based comprehensive single-cell transcriptome analysis technology that enables gene expression profiling of thousands to tens of thousands of individual cells simultaneously. This technology, will enable the capture of data regarding the small fraction of transformed cells present in the pre-disease state, elucidation of the characteristics and roles of the individual cells that make up inflamed tissues, and in combination with informatics approaches, the generation of models of the interactions between large numbers of individual cells. Furthermore, by incorporating spatio-temporal data for each individual cell into these cellular interaction models it is anticipated that it will be possible to reconstruct inflamed tissues at single-cell resolution.
Objectives of the research project
In this research project, we intend to create a model of the cellular society of inflammation that encapsulates the origins, prolongation and irreversibility of inflammatory disease. This model will integrate the molecules, cells, signaling pathways and metabolic pathways that contribute at each stage in the progression of chronic inflammation, from its origins in exposure to various internal and external stressors. By defining the turning points of a disease in terms of quantitative molecular and cellular information, we expect to create a new form of preventive medicine that reveals how those turning points can be controlled. In addition, we aim to unravel the mechanisms behind fibrosis, one of the greatest enigmas of medical research into protracted inflammation, and thus find ways to prevent and regulate this disease. To do this, with comprehensive single-cell transcriptome analysis as a common technology, we will divide the project into the following three research topics, with close collaboration between researchers from each topic.
Topic A01 – Establishment of the cellular society of inflammation for chronic inflammatory disease: We will collect single-cell transcriptome data together with spatio-temporal information in a range of disease models with different pathogeneses and affecting different organs, thus defining the origin, pre-disease condition, progression and irreversible changes (e.g. fibrosis) of each disease. We will also validate novel therapeutic targets and models arising from this work.
Topic A02 – Regulation of the cellular society of inflammation by environmental factors and establishment of molecular targets for preventive therapies: We will investigate the links between physiological factors such as environmental stress, genetic factors, shear stress, hypoxic stress and aging, chronic inflammation, and lifestyle-related diseases, thereby identifying molecular targets that regulate the cellular society of inflammation.
Topic A03 – Socio-cellular informatics: We will develop new methods for analyzing and integrating data from a range of sources including comprehensive single-cell transcriptome data, and construct models that simulate chronic inflammatory disease.
