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Megan Vitko Dissertation 2.pdf (2.55 MB)

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Intestinal Dysfunction in Cystic Fibrosis

Vitko, Megan Sue
http://orcid.org/0000-0002-1062-7144
http://rave.ohiolink.edu/etdc/view?acc_num=case1459248266

Abstract Details

2016, Doctor of Philosophy, Case Western Reserve University, Genetics.
Intestinal Dysfunction in Cystic Fibrosis Abstract By MEGAN VITKO Cystic Fibrosis (CF) is an autosomal recessive genetic disease that is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR protein is an anion channel and loss of CFTR function impedes transepithelial chloride permeation leading to dehydration and the accumulation of thick, sticky mucus in vital organs. Many symptoms occur as a result of non-functional CFTR; however mucus accumulation is a hallmark of CF. CF is a systemic disease that most commonly affects the lungs, pancreas, and gastrointestinal system. Severe lung disease is the major cause of morbidity and mortality associated with CF. There have been many advances in CF diagnosis and treatment since CF was initially described and the continued development of treatments and therapies has increased the predicted survival of patients born today to over 40 years old. However, patients still develop symptoms of CF that decrease their quality of life. GI symptoms of CF are a major concern for patients today as they may be lethal if untreated, affect patients of any age, and may greatly decrease the quality of life for patients. Intestinal complications of CF may include Meconium Ileus (~10-25%), Distal Intestinal Obstruction Syndrome (~10-20%), Small Intestine Bacterial Overgrowth (~30-50%), and failure to thrive (~ 25-30%). Many factors, such as pancreatic insufficiency, modifier genes, and the environment, may contribute to the incidence of intestinal symptoms, thus the origin of CF intestinal manifestations is complex and not well understood. Even though CF has been extensively studied, the exact mechanism behind the development of intestinal symptoms remains to be elucidated. It was previously hypothesized that absence of CFTR in the intestinal epithelium was the main cause of intestinal obstruction, however work in our lab showed that absence of CFTR is necessary, but not sufficient to be the sole cause of intestinal obstruction. I analyzed the role of CFTR in the smooth muscle via the use of conditional mouse models that had Cftr inactivated only in the smooth muscle. I determined that Cftr in the smooth muscle contributes to the development of intestinal obstruction. However, absence of Cftr in the intestinal epithelium and smooth muscle together contribute to the development of CF-like intestinal obstruction rates. I have shown that absence of Cftr in the intestinal epithelium leads to dehydration and mucus accumulation and absence of Cftr in the smooth muscle leads to decreased muscle contraction. The decreased muscle contraction may be due to an impairment in calcium reuptake in the sarcoplasmic reticulum. My work provided novel insight into the origin of CF intestinal manifestations. It is known that CF symptoms, including intestinal obstruction are influenced by modifier genes. Genome wide association studies (GWAS) have identified variants in potential modifier genes, however these studies do not provide information about how these variants modify the symptoms or gene expression. Functional studies are required to test the identified variants and determine how they alter CF symptoms. A GWAS of Meconium Ileus (MI) in CF identified variants in the gene solute carrier family 26, member 9 (SLC26A9) as a potential modifier of intestinal obstruction. I utilized CF mouse models and functionally tested the effects on reduction of Slc26a9 function. I determined that reduction of one copy of Slc26a9 increased intestinal obstruction rates in the CF mice. I also utilized human epithelial cells and showed that single nucleotide polymorphisms in SLC26A9 identified via GWAS of MI in CF correlated with decreased SLC26A9 mRNA expression. Decreased SLC26A9 expression may lead to increased intestinal cellular proliferation, which may contribute to the increase in intestinal obstruction seen in the CF mouse model with a reduction of Slc26a9. My work provided evidence that SLC26A9 may prove to be a potential therapeutic target for CF intestinal obstruction. There are several treatment options available for patients with intestinal obstruction, however not all treatments alleviate complications in all patients and some treatments have negative side effects. It is necessary to develop and test new treatments that may safely alleviate CF patients of intestinal obstruction. I tested a novel guluronate oligomer, OligoG, to determine if drug treatment alleviated CF mouse models of intestinal manifestations. I determined that drug treatment did improve intestinal obstruction, decreased intestinal transit time, and decreased mucus accumulation in CF mice. OligoG may be working as a calcium chelator and sequestering calcium from the mucins, which allows for proper unfolding of the mucins. Proper unfolding of mucins then creates mucus that is easily removed from the lumen. My work provided evidence that OligoG may help alleviate patients of CF intestinal obstruction. A better understanding of the mechanisms behind the development of CF intestinal obstruction, as well as how to alleviate patients of the obstruction, is necessary to improve the quality of life of CF patients. This thesis provides novel insight into the origin of intestinal obstruction, how a potential modifier gene influences intestinal obstruction, and how a novel drug may be used to prevent intestinal obstruction in CF patients.
Craig Hodges, PhD (Advisor)
Darrah Rebecca , PhD (Committee Chair)
Drumm Mitchell , PhD (Committee Member)
Sferra Thomas , MD (Committee Member)
Mitchell Anna , MD, PhD (Committee Member)
197 p.
Genetics
CFTR; Intestinal Obstruction; Cystic Fibrosis; mouse models

Recommended Citations

Citations

  • Vitko, M. S. (2016). Intestinal Dysfunction in Cystic Fibrosis [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1459248266

    APA Style (7th edition)

  • Vitko, Megan. Intestinal Dysfunction in Cystic Fibrosis. 2016. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1459248266.

    MLA Style (8th edition)

  • Vitko, Megan. "Intestinal Dysfunction in Cystic Fibrosis." Doctoral dissertation, Case Western Reserve University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1459248266

    Chicago Manual of Style (17th edition)

case1459248266
439
© 2016, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.