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MECHANOBIOLOGY OF BRAIN-DERIVED CELLS DURING DEVELOPMENTAL STAGES

Mahajan, Gautam
http://rave.ohiolink.edu/etdc/view?acc_num=csu1578332547849308

Abstract Details

2019, Doctor of Philosophy in Engineering, Cleveland State University, Washkewicz College of Engineering.
Development of nervous system has been greatly explored in the framework of genetics, biochemistry and molecular biology. With the growing evidence that mechanobiology plays a crucial role in morphogenesis, current studies are geared towards understanding the role of mechanical cues in nervous system development and progression of neurological disorders. Formation, maturation and differentiation of various development related cells are sensitive to extrinsic and intrinsic perturbations. Based on this hypothesis, the objective of this study was to investigate the effects of environmental toxicants, mutations in molecular clutch proteins, and matrix stiffness cues on the biophysical, biomechanical, and phenotypic changes in brain-derived neural progenitor cells (NPCs) and microglia. In the first aim, we established the utility of biophysical and biomechanical properties of NPCs as indicators of developmental neurotoxicity. Significant compromise (p < 0.001) in NPC mechanical properties was observed with increase in concentration (p < 0.001) and exposure duration (p < 0.001) of four distinct classes of toxic compounds. We propose the utility of mechanical characteristics as a crucial maker of developmental neurotoxicity (mechanotoxicology). In the second aim, we elucidated the critical role of molecular clutch proteins, specifically that of kindlin-3 (K3) in murine brain-derived microglia, on the cell membrane mechanics and physical characteristics. Using genetic knockouts of K3 and AFM analysis, we established the role of K3 in regulating microglia membrane mechanics.Mutation at the K3-β1 integrin binding site revealed that the connection serves as the major contributor of membrane to cortex attachment (MCA). Finally, in aim 3, we identified the molecular mechanisms (non-muscle myosin II) by which NPCs transduce mechanical input from external substrate into fate decisions such as differentiation and phenotype. We established cell mechanics as a label-free marker of differentiation and mechano-adaptation as possible mechanism of differentiation. Mechanical, phenotypical, and genotypical characteristics of brain-derived cells and molecular mechanisms of mechanotransduction established in this dissertation will provide important insights in various cell processes such as morphogenesis, brain plasticity, wound healing, cancer metastasis, and disease progression.
Chandra Kothapalli (Advisor)
Moo-Yeal Lee (Committee Member)
Nolan Holland (Committee Member)
Xue-Long Sun (Committee Member)
Parthasarathy Srinivasan (Committee Member)
Biomechanics; Biomedical Engineering; Biomedical Research; Biophysics; Engineering; Materials Science; Mechanics; Neurosciences
Atomic Force Microscope, Mechanobiology, Biomechanics, Biophysics, Cell Mechanics, Neural Progenitor Cells, Neural Stem Cells, Microglia, Glioblastoma, Smooth Muscle Cells, Retina, Spinal Cord, PDMS, Collagen, Toxicology

Recommended Citations

Citations

  • Mahajan, G. (2019). MECHANOBIOLOGY OF BRAIN-DERIVED CELLS DURING DEVELOPMENTAL STAGES [Doctoral dissertation, Cleveland State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=csu1578332547849308

    APA Style (7th edition)

  • Mahajan, Gautam. MECHANOBIOLOGY OF BRAIN-DERIVED CELLS DURING DEVELOPMENTAL STAGES. 2019. Cleveland State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=csu1578332547849308.

    MLA Style (8th edition)

  • Mahajan, Gautam. "MECHANOBIOLOGY OF BRAIN-DERIVED CELLS DURING DEVELOPMENTAL STAGES." Doctoral dissertation, Cleveland State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=csu1578332547849308

    Chicago Manual of Style (17th edition)

csu1578332547849308
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© 2019, all rights reserved.
This open access ETD is published by Cleveland State University and OhioLINK.