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"DEVELOPMENT OF A FRET BASED DIAGNOSTIC ASSAY FOR CHRONIC MYELOGENOUS LEUKEMIA
and
POTENTIAL AND DIFFERING ROLES OF THE CRKII AND CRKL ADAPTOR PROTEINS IN CHRONIC MYELOGENOUS LEUKEMIA"

by
Ahmet Tunceroglu
M.D./Ph.D. Program
B.S. 2004, Cornell University



Thesis Advisor: Raymond B. Birge, Ph.D.

Professor

Department: Biochemistry & Molecular Biology

Thursday, July 22, 2010
MSB E-609b, 2:00 P.M.


Abstract

In the application of targeted small molecule cancer therapy, acquired drug resistance is the ultimate “Achilles’ Heel” of treatment. One need not look further than the treatment modalities for Chronic Myelogenous Leukemia to gain a tremendous understanding and appreciation for the detrimental effect acquired drug resistance can have in cancer therapy. Due to the indolent onset of the condition, patients are often diagnosed while in the chronic phase of CML during a routine physical exam. Though this initial phase is well managed with currently available therapeutics, patients invariably progress to the more advanced and terminal blast crisis, during which patient survival is measured in months.
Diagnoses are made primarily through identification of the Philadelphia chromosome, responsible for the Bcr-Abl translocation, and by identification of the Bcr-Abl translocation product by PCR. Though low levels of Bcr-Abl have been identified in healthy individuals and despite the fact that treatment of CML focuses on inhibition of the Bcr-Abl kinase, presence of the oncogene, rather than activity of the oncoprotein, continues to be the primary method of diagnosis and relapse determination, due to a lack of effective and practical means of detecting Bcr-Abl activity.
In this thesis, we will present a novel assay based on Fluorescent Resonance Energy Transfer that is capable of detecting in vivo Bcr-Abl activity in real-time. The utility of this assay can range from diagnosis and relapse determination, to pharmaceutical drug development and the design of optimally effective treatment regimens.
The FRET assay that will be presented in this report is based on the structure of the adaptor protein CrkII, a Bcr-Abl interaction partner. The second half of this thesis will be in regard to our investigation of the potential function that this adaptor protein CrkII, and its structural homolog CrkL, may have with respect to Bcr-Abl function and the pathogenesis of CML.


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