Inflammatory bowel disease, Crohn's disease, ulcerative col..
Inflammatory bowel disease, Crohn's disease, ulcerative colitis, colorectal carcinoma, adenomatous polyposis coli (APC), cancer of the colon, alterations in the motility of the GI wall, sprue, liver, drug absorption

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School
Colorado State University
Department
Biomedical Science
Course
BMS 460
Professor
D.Rao Veeramachaneni
Semester
Fall

Description
11 October Inflammatory Bowel Disease Crohn’s Disease Chronic granulomatous disease of unknown origin Affects multiple portions of the colon with intervening normal areas; may involve any part of GI tract Hence, called granulomatous colitis and regional colitis The characteristic feature is it extends through all layers of intestinal wall – deep linear ulcers in the bowel wall which may extend into adjacent organs Appears to result from blockage of lymphoid and lymphatic structures in GI wall ~1/3 of all patients also have extra-intestinal inflammatory lesions (in joints, skin, liver, or eyes) Toll-like Receptor 2 (TLR2) and NOD2 Signaling in Crohn’s Disease TLR2 normally binds to peptidoglycans present in the cell wall of commensal and pathogenic GI bacteria. TLR2 binding initiates signaling through the NFκB pathway to activate expression of pro-inflammatory genes. If peptidoglycan is ingested and degraded by enterocytes, a breakdown product (muramyl dipeptide – MDP) can bind to NOD2 (nucleotide-binding oligomerization domain containing 2) protein in the enterocyte cytoplasm and down-regulated TLR2-mediated NFκB signaling. This negative feedback loop is thought to limit the amount of pro- inflammatory cytokines induced by commensal bacteria while preserving the ability to respond to pathogenic bacteria. A small percentage of cases of Crohn’s disease result from mutations in the NOD2 gene that prevent normal down-regulation of NFκB signaling. Ulcerative Colitis A relapsing inflammatory disease of the mucosa of rectum and colon of unknown etiology Frequently accompanies autoimmune diseases Changes are more severe in the rectum and extend for a variable extent in colon Begins at the base of crypts, with eventual invasion of WBC and formation of abscesses in the crypts Large areas of ulceration Symptoms: abdominal pain, diarrhea Treatment Corticosteroids, salicylate analogs Immunomodulating agents Azathiopurine, mercaptopurine There is diffuse involvement of the intestine, but the colon shows marked ulceration and pseudopolyposis, which account for the irregularity of the internal intestinal surface Colorectal Carcinoma Most common cancer of the GI tract 90% occur in >50 year olds Familial history in 25% patients May originate in polyps, and thus all neoplastic polyps should be removed prophylactically Predisposing factors: hereditary syndromes, such as Familial adenomatous polyposis coli (mutation of APC tumor suppressor gene) Hereditary nonpolyposis colon cancer (mutation of DNA repair genes) Most colorectal cancers are initially asymptomatic; early detection is the only currently available method for reducing mortality Test for occult blood in feces Colonoscopy Symptoms of colorectal cancers depend on location of the tumor Hematochezia – blood stools Pencil-like stools; narrowed lumen Most cancers develop in the proximal or the distal large intestine Colorectal cancers produce carcinoembryonic antigen (CEA) but this tumor marker cannot be used for screening as it is also produced in other carcinomas However, CEA is monitored following resections – persistently elevated CEA is typically associated with residual cancer and is indicative of poor prognosis. Adenomatous Polyposis Coli (APC) and Cancer of the Colon The APC gene product indirectly regulates transcription of a number of critical cell proliferation genes, through its interaction with the transcription factor β-catenin APC binding to β-catenin leads to ubiquitin-mediated β-catenin destruction Loss of APC function increases transcription of β-catenin targets Cadherins, β-catenin, and tumorigenesis Cadherins are transmembrane proteins that establish cell-to-cell contacts, link to F-actin, and participate in cell signaling The intracellular domain of cadherin is associated with a large protein complex that includes β-catenin. Several signaling pathways determine the dissociation of β-catenin from the cell adhesion complex and regulate nuclear transcription. The kinase GSK3β phosphorylates APC-bound β-catenin and targets its destruction by the 26S proteasome Inactivating mutations in the APC or β-catenin genes affect the degradation of β- catenin. Consequently, excess β-catenin, bound to Tcf3-Lef, induces the expression of proteins leading to tumorigenesis. Normal APC pathway β-catenin is phosphorylated by glycogen synthase kinase 3β (GSK3β) coassembled with APC and axin. A polyubiquitin chain is attached to phosphorylated β-catenin by a ubiquitin-ligase complex Polyubiquitin-phosphorylated β-catenin complexes are degraded by the 26S proteasome Abnormal APC pathway Unphosphorylated β-catenin accumulates in the cell β-catenin does not bind to defective APC (or defective β-catenin does not bind to APC) → no degradation of β-catenin Excess of free β-catenin binds to the Tcf3-Lef transcription factor complex, which translocates to the cell nucleus Alterations in the Motility of GI Wall Achalasia of Esophagus Destruction of the myenteric plexus causing dysregulation of esophageal smooth muscle activity Decreased or absent peristaltic activity in the distal esophagus, impaired LES relaxation, and increased LES pressure Achalasia is most commonly idiopathic, but it can also be seen in Chagas’ disease, which is caused by infection with the protozoan parasite Trypanosoma cruzi (found in South America) Megacolon Can be congenital or acquired Most common cause is prolonged constipation Chagas’ disease may also destroy the myenteric plexus of the colon causing toxic megacolon Hirschsprung Disease Congenital disorder of LI in which autonomic ganglia in the smooth muscle are absent or reduced; both myenteric and submucosal plexuses are involved Also called congenital aganglionic megacolon, results when the normal migration of neural crest cells from cecum to rectum is arrested prematurely or when the ganglion cells undergo premature death Coordinated peristaltic contractions are absent and functional obstruction occurs, resulting in dilation proximal to the affected segment. The disease often coexists with other anomalies, particularly Down syndrome The mechanisms underlying defective neural crest cell migration are unknown, but a genetic component is present in nearly all cases 4% of patients’ siblings are affected; however, simple Mendelian inheritance is not involved in most cases Heterozygous loss-of-function mutations in the receptor tyrosine kinase RET account for the majority of familial cases and ~15% of sporadic cases Malabsorption: Sprue Celiac disease (nontropical sprue) Intolerance to gliadin, a component of wheat protein gluten; hence called gluten- sensitive enteropathy Considered an immune disorder triggered by exposure to gliadin in genetically predisposed individuals
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