15th International Conference and Exhibition on Metabolomics & Systems Biology
National University of Science and Technology, Pakistan
Title: Qualitative modeling of TGF beta-associated biological regulatory network: Insight into renal fibrosis
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Biography: Ayesha W Khan
Kidney fibrosis is an anticipated outcome of possibly all types of progressive Chronic Kidney Disease (CKD). Epithelial- Mesenchymal Transition (EMT) signaling pathway is responsible for production of matrix-producing fibroblasts and myofibroblasts in diseased kidney. In this study, a discrete model of TGF-beta and CTGF was constructed using René Thomas formalism to investigate renal fibrosis turn over. The kinetic logic proposed by René Thomas is a renowned approach for modeling of Biological Regulatory Networks (BRNs). This modeling approach uses a set of constraints which represents the dynamics of the BRN thus analyzing the pathway and predicting critical trajectories that leads to a normal or diseased state. The molecular connection between TGF-beta, smad2/3 (transcription factor) phosphorylation and CTGF (Connective Tissue Growth Factor) is modeled using GenoTech. The order of BRN is CTGF, TGF-B and smad3 respectively. The predicted cycle depicts activation of TGF-B (TGF-β) via. cleavage of its own pro-domain (0, 1, 0) and presentation to TGFR-II receptor phosphorylating smad3 (smad2/3) in the state (0, 1, 1). Later TGF-B is turned off (0, 0, 1) thereby activating smad3 that
further stimulates the expression of CTGF in the state (1, 0, 1) and itself turns off in (1, 0, 0). Elevated CTGF expression reactivates TGF-B (1, 1, 0) and the cycle continues. The predicted model has generated one cycle and two steady states. Cyclic behavior in this study represents the diseased state in which all three proteins contribute to renal fibrosis. The proposed model is in accordance with the experimental findings of the existing diseased state. Extended cycle results in enhanced CTGF expression through smad2/3 and smad4 translocation in the nucleus. The results suggest that the system converges towards organ fibrogenesis if CTGF remains constructively active along with Smad2/3 and Smad4 that plays an important role in kidney fibrosis. Therefore, modeling regulatory pathways of kidney fibrosis will escort to the progress of therapeutic tools and real-world useful applications such as predictive and preventive medicine.