HD Physiology Project—Japanese efforts to promote multilevel integrative systems biology and physiome research

Abstract

The HD Physiology Project is a Japanese research consortium that aimed to develop methods and a computational platform in which physiological and pathological information can be described in high-level definitions across multiple scales of time and size. During the 5 years of this project, an appropriate software platform for multilevel functional simulation was developed and a whole-heart model including pharmacokinetics for the assessment of the proarrhythmic risk of drugs was developed. In this article, we outline the description and scientific strategy of this project and present the achievements and influence on multilevel integrative systems biology and physiome research.

In-silico simulated prototype-patients using TPMS technology to study a potential adverse effect of sacubitril and valsartan

“…The Therapeutic Performance Mapping System (TPMS) is a tool that creates mathematical models of the protein pathways underlying a drug/pathology to explain a clinical outcome or phenotype [4][5][6][7][8][9][10]. These models find MoAs that explain how a Stimulus (i.e.…”

“…Defining active/inactive nodes. We define the state of human proteins as active or inactive for a particular phenotype, including its expression (as active) or repression (as inactive) extracted from the GSE57345 gene expression dataset [35] as in Iborra-Egea et al [9] (see further details in supplementary material).…”

“…TPMS incorporates data from different resources and uses the information from the drugs and diseases under study to generate multiple models of potential MoAs. In the last years, TPMS has been broadly used in different clinical areas and with different objectives [5][6][7][8][9][10][11][12], in some cases being validated in the posterior experiments [6,11,12]. Our working hypothesis is that a set of MoAs can represent the different responses to a drug in cells and that a real population of patients is the result of a myriad of cell responses.…”

“…Consequently, it triggers the natriuretic peptide system by inhibiting neprilysin (NEP) and inhibits renin-angiotensin-aldosterone system by blocking the type-1 angiotensin II receptor (AT1R) [15]. In a previous work, TPMS was already applied to unveil the MoA of sacubitril/ valsartan synergy, revealing its effect against two molecular processes [9]: the left ventricular extracellular matrix remodeling, mediated by proteins like gap junction alpha-1 protein or matrix metalloproteinase-9; and the cardiomyocyte apoptosis, through modulation of glycogen synthase kinase-3 beta. However, several publications warned about the potential longterm negative implications of using a neprilysin inhibitor like sacubitril [15][16][17][18][19].…”

PASI: A novel pathway method to identify delicate group effects

“…PASI is less suited for mechanistic studies where the focus is on detecting few pathways which differ in their activity between the test groups or revealing information about mechanisms behind the conditions. Since PASI is designed to be robust to limited uncertainty in pathway structures, it is currently not sensitive to detect whether assumed structures are incomplete, which is a different research topic with its own methods [ 37 ].…”