Case Western Reserve University
Vitko, Megan Sue.
Intestinal Dysfunction in Cystic Fibrosis.
Degree: PhD, Genetics, 2016, Case Western Reserve University
Intestinal Dysfunction in Cystic FibrosisAbstract By
MEGAN VITKOCystic 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…
Advisors/Committee Members: Hodges, Craig (Advisor), Rebecca , Darrah (Committee Chair).
Subjects/Keywords: Genetics; CFTR; Intestinal Obstruction; Cystic Fibrosis; mouse models
to Zotero / EndNote / Reference
APA (6th Edition):
Vitko, M. S. (2016). Intestinal Dysfunction in Cystic Fibrosis. (Doctoral Dissertation). Case Western Reserve University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=case1459248266
Chicago Manual of Style (16th Edition):
Vitko, Megan Sue. “Intestinal Dysfunction in Cystic Fibrosis.” 2016. Doctoral Dissertation, Case Western Reserve University. Accessed August 22, 2019.
MLA Handbook (7th Edition):
Vitko, Megan Sue. “Intestinal Dysfunction in Cystic Fibrosis.” 2016. Web. 22 Aug 2019.
Vitko MS. Intestinal Dysfunction in Cystic Fibrosis. [Internet] [Doctoral dissertation]. Case Western Reserve University; 2016. [cited 2019 Aug 22].
Available from: http://rave.ohiolink.edu/etdc/view?acc_num=case1459248266.
Council of Science Editors:
Vitko MS. Intestinal Dysfunction in Cystic Fibrosis. [Doctoral Dissertation]. Case Western Reserve University; 2016. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=case1459248266