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Identifying Small Molecule Inhibitors and Functional Analysis of PLCgamma in Drosophila melanogaster
Başlık:
Identifying Small Molecule Inhibitors and Functional Analysis of PLCgamma in Drosophila melanogaster
Yazar:
Naidu, Chitra Upendra, author.
ISBN:
9780355990386
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (208 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Justin R. Thackeray Committee members: Denis A. Larochelle; Néva Meyer.
Özet:
PLC-gamma is a secondary signaling molecule and plays a key role in cellular growth, proliferation and apoptosis. Overexpression of mammalian PLC-gamma is linked to tumorigenesis and the transition of primary tumors to metastatic. In the following dissertation, I attempt to find a small molecule inhibitor of PLC-gamma and investigate the role of its individual domains using Drosophila melanogaster as a model organism.
Small wing (Sl), the only D. melanogaster homolog of mammalian PLC-gamma is a multi-domain protein ubiquitously expressed during all stages of development. It is thought to be a negative regulator of the EGFR pathway required for photoreceptor and vein recruitment and a positive regulator of the insulin pathway needed for overall growth. A complete picture of how Sl affects multiple pathways and the importance of its highly conserved domains in these functions is still not completely understood. Phenotypically, Sl null mutants show extra R7 photoreceptors in the eye and smaller wings.
I screened 1,596 small molecules provided by the National Cancer Institute to identify Sl inhibitors using these easily discernible phenotypes in D. melanogaster models. After a series of preliminary, secondary and tertiary screens, I identified three small molecules as potential inhibitors of Sl. In addition, I characterize the role of some of the conserved domains in photoreceptor differentiation by co-expressing constructs mutant for these domains. I found that the conserved tyrosine residue at position 818 is indispensable to R7 photoreceptor recruitment while the W949R mutation affecting the PH-C domain is dominant negative. I also looked at the overexpression of wildtype Sl and found that the D. melanogaster EGFR pathway is inhibited further. Using these results in addition to what we already know about mammalian PLC-gamma activation, I present a model for the mechanism of how Sl functions.
Notlar:
School code: 0048
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(678932.1) | 678932-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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