Browsing by Subject "Cellular Microenvironment"
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Item Balancing Renewal and Differentiation of Progenitor Cells in the Developing Kidney(2017-11-30) Ramalingam, Harini; Marciano, Denise; Carroll, Thomas J.; Cleaver, Ondine; Olson, Eric N.Mammalian kidneys perform the important function of blood filtration. All the filtered wastes are concentrated into urine and excreted from the body. The kidney performs these functions through individual functional units called nephrons. While nephron number may decrease during one's lifetime (due to various kidney injuries or hypoxic events), new nephrons do not form in adults. This is most likely due to the absence of nephron precursor cells. If nephron number falls below a certain threshold, the kidneys stop functioning properly pre-disposing individuals to a myriad of medical conditions including renal failure. While dialysis is a treatment option, the survival rate of a dialysis patients is poor. Currently, kidney transplantation is the only long-term treatment possible, but sufficient numbers of transplantable kidneys are not available. Various stem cell therapies and kidney re-engineering are actively being pursued as viable treatment paths. For successful progress in those approaches, we need access to lots of progenitors. To obtain this a thorough understanding of kidney development and the various signals that play important roles in nephron endowment is imperative. Despite many decades of work invested in this field, there are still many unknowns. Regulation of renewal and differentiation of the progenitors during the process of nephron formation is the focus of my dissertation.Item Mechanical Regulation of Glycolysis via Cytoskeleton Architecture(2019-11-14) Park, Jin Suk; Bachoo, Robert; Danuser, Gaudenz; DeBerardinis, Ralph J.; Shay, Jerry W.The mechanical properties of the microenvironment continuously induce cells to modulate functions like growth, survival, apoptosis, differentiation, and morphogenesis. These adaptations rely on dynamic cytoskeletal remodeling and actomyosin contractility. Although all these processes are coupled to energy consumption, it is unknown if and how cells metabolically adapt to mechanical cues. In this thesis, I demonstrate that phosphofructokinase (PFK), a rate-limiting regulator of glycolysis, responds to mechanical cues in human bronchial epithelial cells (HBECs). Transferring HBECs from stiff to soft substrates causes downregulation of glycolysis via degradation of PFK. The loss of PFK expression is triggered by stress fiber disassembly, which releases the PFK-targeting E3 ubiquitin ligase, tripartite motif(TRIM)-containing protein 21 (TRIM21). Transformed non-small cell lung cancer cells (NSCLCs), which maintain high glycolytic rates regardless of changing mechanical cues, retain PFK expression by downregulating TRIM21, and by sequestering residual TRIM21 to a stress fiber population that is insensitive to substrate stiffness. Thus, I dissected a mechanism by which glycolysis responds to architectural features of the actomyosin cytoskeleton, coupling cell metabolism to the mechanical properties of the surrounding tissue. These processes enable normal cells to modulate energy production in variable microenvironments, while the resistance of the cytoskeleton to respond to extracellular mechanical cues allows high glycolytic rates to persist in cancer cells despite constant alterations of the tumor tissue.