京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22001号 / 医博第4515号 / 新制||医||1038(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 井上 治久, 教授 林 康紀, 教授 高橋 淳 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第17896号 / 農博第2019号 / 新制||農||1017(附属図書館) / 学位論文||H25||N4792(農学部図書室) / 30716 / 京都大学大学院農学研究科応用生物科学専攻 / (主査)教授 菅原 達也, 教授 左子 芳彦, 教授 澤山 茂樹 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・論文博士 / 博士(農学) / 乙第12880号 / 論農博第2807号 / 新制||農||1028(附属図書館) / 学位論文||H26||N4879(農学部図書室) / 31598 / (主査)教授 河田 照雄, 教授 金本 龍平, 教授 谷 史人 / 学位規則第4条第2項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

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This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

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My Ph.D. research project in the Bhagwati Gupta lab focuses on understanding the mechanism by which the Axin family of scaffolding proteins functions to regulate biological processes in multicellular eukaryotes. Towards this, I am using the nematode (worm) Caenorhabditis elegans as an animal model to investigate the role of one of the Axin homologs, PRY-1. Studies in various model systems and humans have shown that the Axin family of proteins plays crucial roles during cell proliferation, cell differentiation, and organ formation. Such a role of Axin depends on the negative regulation of the WNT signaling cascade. Consistent with these, alterations in Axin function are associated with developmental abnormalities and age-associated diseases such as axis duplication, neuroectodermal defect, and muscle degeneration. As a scaffolding protein, Axin family members bind to and recruit multiple protein partners that are both WNT dependent and independent. However, how Axin interacts with these factors to regulate molecular events is not well understood. While some Axin-interacting factors have been identified, many more remain to be discovered. My project deals with the identification and functional characterization of pry-1/Axin interactors in C. elegans. The key findings of my Ph.D. research are published in five peer-reviewed papers. Collectively, the results demonstrate that PRY-1 is necessary to regulate lipid metabolism, stress response, muscle health, and aging. I have shown that PRY-1 utilizes multiple pathways to control these diverse processes. Specifically, PRY-1 functions via the SREBP transcription factor homolog SBP-1 to regulate yolk lipoprotein expression to promote lipid synthesis. The analysis of pry-1’s role in aging and muscle health has revealed its interactions with the energy sensor AMPK homolog AAK-2, thereby affecting the function of the Insulin/IGF1 signaling (IIS) transcriptional regulator DAF-16/FOXO. Moreover, I have identified several mRNA genes and microRNAs that function downstream of PRY-1/Axin signaling to either suppress or enhance pry-1 mutant defects. All these novel interactors have mammalian homologs. Altogether, these findings form the basis to pursue future work to investigate the conserved mechanism of Axin signaling and hold the potential for effective intervention to delay aging and age-associated muscle deterioration. / Thesis / Doctor of Philosophy (PhD)

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