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AN INQUIRY OF THE SR/CR MOUSE PHENOTYPE AND ADVANCES REGARDING THE SEARCH FOR AN ANALOGOUS HUMAN TRAIT

Electronic Theses and Dissertations

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abstract
In 1999, researchers within our laboratory observed the unique occurrence of cancer resistance in a single BALB/c mouse. Subsequent breeding studies found that this trait, known as Spontaneous Regression/Complete Resistance (SR/CR) is heritable among 30 to 40 % of offspring in an autosomal manner, thus enabling extensive characterization studies to occur among a colony record comprising over 12,000 mice to date. These studies indicated that SR/CR cancer resistance is mediated by a massive infiltration of predominantly innate leukocyte subpopulations that are capable of serving as a therapeutic treatment to both subcutaneously established and genetically endogenous mouse models of cancer. Also, the in vitro assessment of cancer killing activity (CKA) among isolated naïve leukocytes is capable of predicting SR/CR cancer resistance among offspring. The success of such therapies, and the in vitro ability to predict cancer resistance in mice has motivated us to search for an analogous measure of CKA among isolated human leukocytes. Presented here, are the results of a pilot study that intended to investigate the existence of CKA among both healthy participants and those with cancer. Additionally, novel analytical tools are described in which to derive CKA using a high-throughput real-time cellular detection system. Also, although the SR/CR phenotype is observably heritable, past genetic investigations have failed to elucidate a clear genetic explanation of its cause. In order to provide future accessibility and analysis to the record of inheritance, a detailed database was created that summarizes screening results of each mouse generated within the SR/CR colony. Furthermore, in order to advance our understanding of the mechanism of SR/CR cancer resistance, a comparative transcriptome analysis was carried out using a recently adapted form of next generation sequencing technologies (RNA-Seq). An initial analysis revealed several potentially distinguishing molecular markers of the SR/CR cancer resistant phenotype. Among this set of markers was a nuclear receptor (Rorc) that was expressed approximately 45 times higher within neutrophils of SR/CR mice when compared to WT samples. In summary, these results provide both novel methods and evidence that further characterizes the SR/CR cancer resistant phenotype and demonstrate the presence of CKA within humans, while also providing tools with which to enhance its use and understanding.
subject
Cytotoxicity
Immunosurveillance
Leukocytes
RNA-Seq
SR/CR Mouse
contributor
Blanks, Michael J. (author)
Cui, Zheng (committee chair)
Ornelles, David (committee member)
Howard, Timothy (committee member)
Kute, Timothy (committee member)
Willingham, Mark (committee member)
date
2011-02-16T21:42:26Z (accessioned)
2010 (issued)
degree
Molecular Genetics & Genomics (discipline)
2020-03-19 (liftdate)
embargo
2020-03-19 (terms)
identifier
http://hdl.handle.net/10339/30410 (uri)
language
en (iso)
publisher
Wake Forest University
title
AN INQUIRY OF THE SR/CR MOUSE PHENOTYPE AND ADVANCES REGARDING THE SEARCH FOR AN ANALOGOUS HUMAN TRAIT
type
Dissertation

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