Electronic Theses and Dissertations

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Browsing Electronic Theses and Dissertations by Author "Abdel-Rahman, Sherif"

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    Histopathological and Molecular Changes in Intestinal Tissue Following Proton Exposure in Varying Mouse Models
    Purgason, Ashley; Wu, Honglu; Abdel-Rahman, Sherif; Ullrich, Robert; Yu, Yongjia; Hamilton, Stanley R
    Most people are aware that radiation can have negative health consequences for human beings exposed to the phenomena. These negative outcomes are dependent upon dose, dose rate, the individual’s genetic makeup and other factors. Many people do not know, however, that radiation is present constantly in the background of space, posing significant risks for astronauts traveling beyond the low Earth orbit. Protons, one form of charged particle energy, account for the greatest composition of space radiation. Scientists must better understand the aforementioned risks in order to properly counsel astronauts and health care providers about the possibilities of diseases such as cancer following radiation exposure in space flight. Low dose radiation exposure to gamma rays and protons is a much more common exposure in daily life and for astronauts in flight as opposed to high doses like those used in radiation therapy for cancer treatment. The three strategies proposed here utilize an in vivo model, specifically mice, to better extrapolate awareness of the biological consequences of low dose radiation exposure to the space flight setting and determine at the genetic level how low dose exposures differ in the radiosensitive gastrointestinal tract from high dose exposures. The gastrointestinal tract is important to study with regard to space flight for many reasons including the sensitivity of the small intestine to ionizing radiation, the high frequency of colon cancer development in the Western world, and the fact that the brave men and women who don a space suit are typically middle aged and may harbor pre-cancerous lesions even prior to irradiation. Radiation could exacerbate a cancerous event in a cell. Determining exactly which genes are being up- or down-regulated in responses after varying radiation doses and qualities can establish connections between pathways previously unknown and hopefully elucidate molecular insight into the early disease processes associated with irradiation. The significance of this study is provided in that the knowledge obtained here can be used to better select low dose radiation exposure limits, discover effective counter-measures against the harmful effects of radiation, and potentially even discern novel and favorable uses of radiation for humans.
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    XPC Haplotypes Alter DNA Repair Capacity and Levels of Genetic Damage
    Rondelli, Catherine Michelle; Abdel-Rahman, Sherif; Wickliffe, Jeffery; El-Zein, Randa; Barral, Jose; Anderson, Karl; Ward, Jonathan
    Xeroderma pigmentosum complementation group C (XPC) is the key recognition factor of DNA damage in global genome nucleotide excision repair (NER). The disease Xeroderma pigmentosum (XP) results from mutations leading to structural defects of the encoding gene and in some instances trace to changes in a single nucleotide. The XPC gene is highly polymorphic and while polymorphisms in general have no discernible phenotypic effects, some can alter the structure and function of the encoded protein. To date, the effect of single nucleotide polymorphisms (SNPs) in XPC have not been properly characterized. Documented associations exist between only a few XPC SNPs and cancer risk, leaving a majority of SNPs untested. My hypothesis is that specific XPC SNP combinations (haplotypes) alter DNA repair capacity and levels of genetic damage by altering transcriptional processes and/or protein function. I used bioinformatics to conduct a comprehensive haplotype analysis of the entire genomic sequence of XPC and characterize the effect of haplotypes on genetic damage in a population of smokers as an environmentally exposed population. All genomic region XPC polymorphisms with a minor allele frequency (MAF) ≥0.05, from the HapMap CEPH population were analyzed using PHASE, generating a series of likely phylogenetically clustered haplotypes. Cigarette smokers and matched non-smokers from a White, non-Hispanic population residing in the Houston-Galveston area were genotyped and recoded for these haplotype groups. Association between smoking status and DNA damage was determined using chromosomal aberrations as a biomarker. To characterize the biological effects of the XPC haplotypes, I determined how they affected DNA damage and repair capacity over time (i.e. the genotype/phenotype relationship) using representative cell lines. I evaluated the effect of these haplotypes on NER capacity using ELISA (Enzyme Linked Immunosorbent Assay) following exposure to ultraviolet (UV) radiation. I characterized the functional significance of XPC haplotypes by determining the effects of these haplotypes on transcriptional processing and stability using real-time analysis, and protein expression and stability with Western blot analysis. I found that the haplotypes not only conferred differential repair capacity, but that they did so through uniquely different mechanisms.