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150527- Rymut Thesis.pdf (4.23 MB)

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Microtubule Regulation in Cystic Fibrosis Pathophysiology

Rymut, Sharon Marie
http://orcid.org/0000-0002-6306-0591
http://rave.ohiolink.edu/etdc/view?acc_num=case1432730616

Abstract Details

2015, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
Cystic fibrosis (CF)-related inflammation remains an obstacle in CF treatment and a leading cause for lung disease as the mechanism underlying inflammation is not well understood. It has been established that CF systems consist of a loss of endosomal transport exemplified by perinuclear cholesterol accumulation, contributing to altered signaling and pro-inflammatory events. It is hypothesized that microtubule stability as analyzed through a decrease in microtubule acetylation and microtubule polymerization rates contribute to the loss of endosomal transport and increased inflammation. One potential contributing factor to these transport issues is the scaffolding protein ßarr2. Studies show that ßarr2 is upregulated due to disrupted microtubule structures, consequence of dysfunctional CFTR and not due to its assumed role in down-regulation of adrenergic receptors. These findings led to the discovery that microtubule acetylation is decreased in CF cells and tissues. Reestablishment of microtubule acetylation through HDAC6 inhibition revealed the reversal of downstream CF phenotypes, including perinuclear cholesterol accumulation, increased RhoA expression, and NF-¿B activation. Additional characterization of HDAC6 inhibition in ¿F508 mice (¿F508/HDAC6) confirmed the pivotal role of microtubule acetylation levels on CF phenotypes, including RhoA expression, growth regulation (height and weight), survival, and response to bacterial challenge. Further investigation of microtubule regulation revealed that microtubule dynamics of CF epithelial cells are also compromised. Both cultured and primary human nasal epithelial (HNE) cells have decreased microtubule polymerization rates due to dysfunctional CFTR. To reestablish microtubule polymerization rates, exchange protein activated by cAMP (EPAC1) was investigated because of its known modulation of microtubule dynamics and its responsiveness to cAMP. Earlier work from the Kelley lab ties EPAC1 to cAMP control of cholesterol accumulation. It was determined that activation of EPAC1 is sufficient to correct microtubule polymerization rates, restore transport, and normalize signaling. These studies established that microtubule stability and dynamics are compromised in CF epithelial cells as a direct consequence of dysfunctional CFTR and their improper modulation contributes to pro-inflammatory profiles. By being able to target microtubule stability through HDAC6 and consequently impacting on inflammatory and other signaling pathways, this work enhances the knowledge of CF pathophysiology and the future of CF therapeutics.
Thomas Kelley (Advisor)
Paul MacDonald (Committee Chair)
Ruth Siegel (Committee Member)
Craig Hodges (Committee Member)
Danny Mannor (Committee Member)
Rebecca Darrah (Committee Member)
Pharmacology

Recommended Citations

Citations

  • Rymut, S. M. (2015). Microtubule Regulation in Cystic Fibrosis Pathophysiology [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1432730616

    APA Style (7th edition)

  • Rymut, Sharon. Microtubule Regulation in Cystic Fibrosis Pathophysiology . 2015. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1432730616.

    MLA Style (8th edition)

  • Rymut, Sharon. "Microtubule Regulation in Cystic Fibrosis Pathophysiology ." Doctoral dissertation, Case Western Reserve University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1432730616

    Chicago Manual of Style (17th edition)

case1432730616
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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.