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Analysis of the cell-adhesion signaling network and its crosstalk with the epidermal growth factor pathway in primary rat hepatocytes
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Andrianarijaona, Tsirisoa. Analysis of the cell-adhesion signaling network and its crosstalk with the epidermal growth factor pathway in primary rat hepatocytes. Retrieved from https://doi.org/doi:10.7282/T3BR8Q66

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TitleAnalysis of the cell-adhesion signaling network and its crosstalk with the epidermal growth factor pathway in primary rat hepatocytes
NameAndrianarijaona, Tsirisoa (author); Roth, Charles M (chair); Moghe, Prabhas (internal member); Shinbrot, Troy (internal member); Nanda, Vikas (internal member); Yakoby, Nir (outside member); Rutgers University; Graduate School - New Brunswick
Date Created2013
Other Date2013-10 (degree)
SubjectBiochemistry, Liver cells--Differentiation, Rats--Physiology
Extentxii, 127 p. : ill.
DescriptionCultured primary hepatocytes provide excellent platforms for the experimental study of the toxicology and the metabolism of various potentially harmful compounds. However, the usefulness of primary hepatocytes is significantly hampered by their loss of specific functions in vitro through a process called dedifferentiation. In general, dedifferentiation results from the loss of the normal balance of proliferation and differentiation, which are mutually exclusive in vitro. Therefore, a clear understanding of the mechanisms that drive hepatocyte proliferation in culture would certainly provide valuable information for the design of new cell culture systems. This doctoral dissertation is focused on understanding the dynamical properties of the rat hepatocyte-adhesion signaling network and its crosstalk with the MAPK/ERK pathway. A major part of this thesis was focused on designing a mathematical model of the coupled integrin and E-cadherin/-catenin signaling pathways to analyze the property of their underlying control system. Combining bifurcation analysis with single-cell measurements, this study provided the evidence that the hepatocyte adhesion pathways exhibit a bistability in response to changes in PIP2 cellular levels, and thereby may undergo a switch between a strong integrin-based/weak E-cadherin-based adhesion, and a weak integrin-based/strong E-cadherin-based adhesion. Rat hepatocytes secrete fibronectin in culture, and this study showed that the strong integrin-based adhesion resulted from a fibronectin-mediated activation of the integrin pathway. A strong integrin-based adhesion primes the hepatocytes for a maximal responsiveness to EGF, which was characterized by a sustained activation of the MAPK/ERK pathway in mid G1 and the ensuing full cell commitment to proliferation. The adhesion-dependent priming was characterized by an upregulation of certain MAPK/ERK activators. The overall results from this dissertation provide a better insight into the design of novel hepatocyte culture systems that will be more conducive to the preservation of hepatocyte differentiation. Additionally, the mathematical model that was designed in this study provides a foundation for future in-depth studies of the cell-adhesion network in various cell types.
NotePh.D.
NoteIncludes bibliographical references
Noteby Tsirisoa Solon'i Aina Andrianarijaona
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T3BR8Q66
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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