DECIPHERING THE ROLE OF CELL-CELL COMMUNICATION IN HEALTH AND DISEASE - USING SYSTEMS BIOLOGY BASED COMPUTATIONAL MODELLING

Cell-cell communication plays a significant role in shaping the functionality of the cells.
Communication between the cells is also responsible for maintaining the physiological state of the
cells and the tissue. Therefore, it is important to study the different ways by which cell-cell
communication impacts the functional state of cells. Alterations in cell-cell communication can
contribute to the development of disease conditions. In this thesis, we present two computational
tools and a study to explore the different aspects of cell-cell communication. In the first
manuscript, FunRes was developed to leverage the cell-cell communication model to investigate
functional heterogeneity in cell types and characterize cell states based on the integration of interand intra-cellular signalling. This tool utilizes a combination of receptors and transcription factors
(TFs) based on the reconstructed cell-cell communication network to split the cell types into
functional states. The tool was applied to the TabulaMurisSenis atlas to discover functional cell
states in both young and old mouse datasets. In addition, we compared our tool with state-of-the-art tools and validated the cell states using available markers from the literature. Secondly, we
studied the evolution of gene expression in developing astrocytes under normal and inflammatory
conditions. We characterized these cells using both transcriptional and chromatin accessibility data
which were integrated to reconstruct the gene regulatory networks (GRNs) specific to the condition
and timepoints. The GRNs were then topologically analyzed to identify key regulators of the
developmental process under both normal and inflammatory conditions. In the final manuscript,
we developed a computational tool that identified regulators of allergy and tolerance in a mouse
model. The tool works by first reconstructing the cell-cell communication network and then
analyzing the network for feedback loops. These feedback loops are important as they contribute
to the sustenance of the tissue’s state. Identification of the feedback loops allows for the discovery
of important molecules by comparative analysis of these feedback loops between various
conditions.
In summary, this thesis encompasses various ways of cellular regulation using cell-cell
communication in a tissue. These studies contribute to a better understanding of the role cell-cell
communication plays in health and disease along with the identification of therapeutic targets to
design novel strategies against diseases