Cellular Pathology as the Basis of Disease

Pathology in key cell types leading to profound alterations in the normal physiological behavior of multiple organs collectively drives the onset and progression of complex diseases like T2D and NASH. Our research efforts are focused on developing a detailed articulation of the molecular networks in each of these key cells that drive this patho-physiology across multiple tissues in T2D and NASH. The cell types we have focused on are -Hepatocytes, Beta cells, Adipocytes, Myocytes,  Macrophages, Endothelial cells, Stellate cells, Fibroblasts and Myofibroblasts.

Our primary goal is to identify a subset of “core” molecular networks that are conserved across each of these key cell types and are linked to the patho-physiology in T2D and NASH. Modulating these “core” molecular networks should lead to significant modifications in the pathophysiology thus translating into truly novel therapies in the clinic that can fulfill the significant gaps in the treatment of these diseases.

We have combined a set of computational and in-vitro approaches to develop a unique platform to enable the goals of our Network Biology approach to the cellular pathology of T2D and NASH. At the heart of this platform is a set of computational molecular network models that by integrating signaling, regulatory and metabolic networks capture the physiology of the key cells. Vast amounts of molecular and cellular data painstakingly extracted from peer reviewed literature have been used to build these models. Extensive simulation based studies using these models have helped us generate novel insights and identify the “core” molecular networks driving the pathological responses in each of these cells. Further simulation studies using these models have helped us hypothesise and identify a set of protein targets (combining novel and recently uncovered) that constitute our pipeline.

We have used these network insights to develop a wide array of measurements in cell systems that consist not only of the key cellular outcomes that are altered in disease (cellular pathology) but also of the key molecular pathways  that are driving these alterations. Knowledge of these pathways allow us to incorporate the cellular conditions associated with pathology into these measurements. Across the multiple cell types these unique cell based measurements constitute a library of network assays that collectively constitute the second component of our platform. We have systematically used these assays as “pathology mimicking screens” to not only qualify targets generated by our simulation based studies but to also rigorously select lead compounds in each of the NCE programs in our pipeline.

More recently we have started an effort to identify and qualify sets of secreted proteins and metabolites that are linked to the “core” molecular networks and hence the pathology in each of these key cells. We firmly believe that these biomarkers, that constitute the third element of our platform, can serve as invaluable tools for the development of our NCE programs in the clinic.