Browsing by Author "Lwigale, Peter Yunju"

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    Characterization of Structure and Function Relationship between Domains of the ER Membrane Protein Atlastin
    (2014-02-06) Desai, Tanvi; McNew, James A.; Huang, Huey W.; Braam, Janet; Stern, Michael; Lwigale, Peter Yunju
    The endoplasmic Reticulum (ER) is an important site for lipid synthesis, protein synthesis and transport. ER fusion is an essential process for its maintenance and biogenesis. Mutations in genes involved in this process cause Hereditary Spastic Paraplegia (HSP). These mutations are shown to affect intracellular trafficking and localization of membrane compartment. One of the important proteins causing early onset of HSP is Atlastin. Previous work in McNew lab at Rice University (Moss et al., 2011b) has shown that atlastin is involved in the homotypic fusion of the ER and the C-terminal cytoplasmic region of atlastin is essential for atlastin mediated fusion. During my studies presented in this thesis, I was able to demonstrate that the C-terminal cytoplasmic region of atlastin destabilizes lipid bilayers to facilitate fusion. The requirement of C-terminal cytoplasmic region is minimal when fusing two fluid (or unstable) lipid bilayers. The C-terminal cytoplasmic region of atlastin forms an amphipathic helix and mutations on the hydrophobic phase of the helix reduce fusion. These mutations are not dominant, as presence of full length atlastin on even one of the fusing lipid bilayers can significantly improve fusion during a heterotypic fusion reaction. Additionally, domain swaps between human atlastin-1 and drosophila atlastin show that the role of C-terminal cytoplasmic region is highly conserved. Also, during my research presented here in, I found that when the transmembrane region and C-terminal cytoplasmic region of human atlastin-1 were swapped with drosophila atlastin, it showed functional similarity. These results show that although atlastins in organisms play an important role in the ER fusion, there are likely species specific differences in how this is achieved. An understanding of atlastin mediated fusion should help in unraveling mechanisms of HSP pathogenesis and other disorders arising from dysfunctional ER.
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    FGFR4 and β-Klotho in Metastatic Prostate Cancer
    (2013-07-24) Shenefelt, Derek; Lwigale, Peter Yunju; Farach-Carson, Cindy; Carson, Daniel D.; Wagner, Daniel S.; Qutub, Amina A.
    FGFR4 and β-Klotho in Metastatic Prostate Cancer by Derek LaMar Shenefelt Fibroblast growth factors and fibroblast growth factor receptors have been associated with the aggressiveness and progression of Prostate Cancer (PCa). Also, β-Klotho is a known co-receptor with FGFR4 for FGF19 in the liver however, the role of this co-receptor pair remains unclear in the setting of PCa. I demonstrated that FGFR4 and KLB mRNA and protein are highly expressed in PCa cells when compared to bone marrow stromal cells, a common site of metastasis. I also provide support for the association of FGFR4 and KLB in PCa, suggesting a functional co-receptor pair capable of altering cellular signaling. FGFR4-KLb may also provide some level of protection to PCa cells from chemotherapeutics. This analysis of FGFR4 and KLB expression and signaling in PCa has provided novel insights into phenotypic alterations during PCa progression while also providing new avenues of study to further explore the role and importance of this exciting co-receptor complex.
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    The Plant Circadian Clock Regulates Biotic Stress Resistance and Defense Hormone Levels
    (2013-11-21) Goodspeed, Danielle; Braam, Janet; Lwigale, Peter Yunju; Masiello, Caroline A.; Matthews, Kathleen S.; Olson, John S.
    Diverse life forms have evolved internal clocks enabling them to monitor time and thereby anticipate the daily environmental changes caused by the earth’s rotation. The plant circadian clock regulates expression of about one-third of the Arabidopsis genome, yet the physiological relevance of this regulation is not fully understood. Here we show that the circadian clock, acting with hormone signals, provides selective advantage to plants through anticipation of and enhanced defense against herbivory and pathogen infection. I found that plants entrained in-phase with the herbivore Trichoplusia ni (T. ni) are more resistant than plants entrained out-of-phase. Similarly, when plants are inoculated with Botrytis cinerea (B. cinerea), the time-of-day at which the inoculation initially occurred significantly affects the rate of infection. Both the circadian clock and jasmonates are required for resistance to herbivory and time-of-day resistance to pathogen infection. Jasmonate and salicylate accumulation is circadian regulated, and accumulation patterns are in opposite phase to each other. I also demonstrate that the circadian clock of post-harvest cabbage (Brassica oleracea) is entrainable by light-dark cycles and results in enhanced herbivore resistance. In addition, entrainment of Arabidopsis plants and post-harvest cabbage causes cyclical accumulation of metabolites that function in plant defense. Finally, I show that the phenomenon of post-harvest entrainment and enhanced herbivore resistance is widespread among diverse crops. The evolution of the plant circadian clock not only provides a strong physiological advantage in pest defense but also can enhance the nutritional value of plant-derived food.
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    The Role of Semaphorin/Neuropilin Signaling in the Development of Innervation and Avascularization of the Cornea
    (2012-11-30) McKenna, Chelsey; Lwigale, Peter Yunju; Braam, Janet; Farach-Carson, Cindy; Stern, Michael; Segatori, Laura
    Millions of corneal procedures performed every year and a multitude of corneal diseases can damage the corneal nerves or induce neovascularization into the cornea; a complete understanding of the molecular regulators of nerve and blood growth into the cornea is necessary to help keep this tissue properly innervated and avascular during a disease state. Identifying the developmental regulators that establish avascularity and innervation have great potential for therapeutic use in the adult. The development of corneal innervation has only been studied in the avian system, but current molecular investigations into regulators of innervation and avascularity are done in the mammalian system. I performed a detailed analysis of the development of mammalian corneal innervation. This information can now be used for any future studies in this area. My work has also identified molecular regulators that help to control the development of corneal innervation and vascularization in both the avian and mammalian system. Semaphorin3A (Sema3A) is a known axon repellent and inhibitor of endothelial cell migration. This protein is known to affect avian cornea development, but it is unknown if this molecule affects mammalian cornea development or avascularity. Through the use of immunostaining, in situ hybridization, qRT-PCR, genetic and pharmacological inhibition of Sema3A, and implantation of recombinant Sema3A, I have discovered that Sema3A plays a key role in the timing of innervation into the mammalian cornea, and the development of an avascular cornea in both the avian and mammalian systems. This is the first time Sema3A has shown to be essential in both the mammalian cornea development and in establishing an avascular cornea. This information could serve as a springboard for further investigation into potential therapeutic drugs for diseases of cornea innervation or neovascularization.