Life Sciences & Biotechnology
Title : | Modeling spatial and temporal dynamics of mRNA translation |
Area of research : | Life Sciences & Biotechnology |
Focus area : | Theoretical Sciences, Molecula Biology, Translation of mRNA |
Principal Investigator : | Dr. Rati Sharma, Indian Institute Of Science Education And Research (IISER) Bhopal, Madhya Pradesh |
Timeline Start Year : | 2023 |
Timeline End Year : | 2026 |
Contact info : | rati@iiserb.ac.in |
Details
Executive Summary : | mRNA translation is one of the most important steps in the gene expression (final protein production) taking place within a biological cell. This occurs when the ribosome machinery assembles on the mRNA and successively produces amino acids of the final protein as it moves from codon (sequence of three RNA nucleotides) to codon. The ribosome assembly itself involves coming together of different components from across different parts of the cell. This requires diffusion of the various components of the machinery across a spatially heterogeneous cell, assembling on the mRNA and subsequently undergoing the translation process. This is a fairly complex process which has not yet been understood completely. The main complexity here arises from a span of various timescales and spatial heterogeneities. The project will involve modeling the translation process under the influence of noise from such a spatially heterogeneous system and reproducing the protein production at the end. This is especially significant in the context of a wide distribution of translation initiation rates and hopping rates that have been observed experimentally [Khuperker et al. Nature Protocols 2020, Volkov et al. Methods 2019]. This then leads to a distribution of protein copy numbers being produced in addition to the distribution in the rates of production. The translation mechanism also sometimes determines the localization of proteins on a specific part of the plasma membrane. The entire process therefore needs to be studied in the context of free diffusion and targeted dynamical hopping while accounting for fluctuations due to both the dynamical system and the surrounding environment. Through this proposal, we plan to incorporate a fluctuating dynamical model based on the TASEP formalism of non-equilibrium statistical mechanics and accompanying stochastic simulations that incorporate both facilitated diffusion and search in addition to the various kinetic rates for detachment and attachment of ribosome to the mRNA lattice. The results from the proposed theoretical and computational model will be compared to existing quantitative data from real single molecule experiments to test their validity. The model will then also be used to make new predictions regarding the timescales of ribosome hopping and fall off dynamics on mRNA molecules of varying lengths and existing in varying spatial environments. The model will specifically attempt to answer the following broad questions. Can we develop a unified model that takes into account the various timescales of mRNA translation? How do the distribution of kinetic rates of various processes affect the protein heterogeneity that is observed in single molecule gene expression studies? Can we make a quantitative and experimentally verifiable prediction of the changes in mRNA translation kinetics and protein copy number distribution due to changes in ribosome fall off rates. |
Total Budget (INR): | 6,60,000 |
Organizations involved