The stiffness of the organic material (the matrix) that cells grow on changes numerous cellular functions including migration, proliferation, and differentiation. Using a substrate that provides the correct mechanical cues to cells is a promising approach for enhancing tissue repair/regeneration and facilitating tissue-biomaterials integration. Long non-coding ribonucleic acids (LncRNAs) are messenger molecules that are powerful regulators of cell differentiation, development, and important during the progress of cancers. Since matrix stiffness changes cell functions, the project will test whether stiffness regulates LncRNA production. One important cell change that we think is associated with LncRNA production is the epithelial-mesenchymal-transition (EMT). This is an essential cellular process in development, tissue repair, scar formation, and cancer development that changes whether the cells are quiescent or migratory. This project will identify LncRNAs that are turned on or off in a matrix stiffness-dependent manner under conditions that cause EMT. The overall goal of this research program is to produce transformative contributions to the current understanding of the role of matrix stiffness signals in LncRNA expression and cell differentiation. By enhancing our understanding of how matrix properties regulate gene expression in cells, results of this research will have broad-ranging impacts in fields as diverse as cell-biomaterial interactions, cell mechanotransduction, and molecular and cell biology of gene regulation. The PI will will provide opportunities for undergraduate and graduate students to work on independent projects, and will create a summer course on 'Cell Biomechanics' in collaboration with the University of Maryland's Upward Bound Math-Science program for high school students from underrepresented groups
The objective of this project is to identify and characterize matrix stiffness-sensitive LncRNAs using global expression analysis, and to determine the role of TRPV4 in matrix stiffness-induced LncRNA expression and EMT. Based on the preliminary data, the central hypothesis is that matrix stiffness controls LncRNA expression, and thereby EMT in a manner dependent on TRPV4. Two Specific Aims will test this hypothesis by utilizing molecular strategies involving human and mouse normal primary cells, TRPV4 null and congenic wild-type mice, LncRNA arrays, and in vitro and in vivo models of the EMT. Specific Aim 1 will identify and characterize matrix stiffness-sensitive LncRNAs using in vitro and in vivo model systems. Specific Aim 2 will delineate the association between TRPV4, matrix stiffness-sensitive LncRNAs, and modulation of EMT. When completed, we expect that the results of this study will provide novel information and insight regarding the molecular mechanisms mediating LncRNA expression and EMT.
