MHHD Disease Template 052114 CF FINAL - Showcase day
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Transcript of MHHD Disease Template 052114 CF FINAL - Showcase day
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Cystic FibrosisMechanisms of Human Health and Disease 2015
Bhageerathi GanesanNew Albany High School, Class of 2017Johns Hopkins University, Molecular and
Cellular Biology
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AgendaVital StatisticsOverviewDetailed MechanismCurrent TreatmentsAcknowledgements
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A massive problem from a tiny change
• 1,000 new diagnoses in the US per year (Cystic Fibrosis Foundation); 30,000 affected in US, 70,000 worldwide
• Age-adjusted survival rate among Caucasians: 0.22 per 100,000 (American Lung Association)
• Most common in Europe, regions with residents of European descent
• Susceptible demographics: Predominantly Caucasian population, though found globally
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CF in SummaryImpacts cells lining body
cavities (epithelium)Faulty cellular component,
cells make thick mucusMakes breathing hard,
greater risk of bacterial infections
Clogged duct systems cause digestion/nutrient absorption, sweating problems
Genetic disorder: autosomal recessive inheritance
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Chief Mechanisms: A Molecular Model• Deletion mutation on
chromosome 7• CFTR channel protein
incorrectly formed and folded, does not reach membrane
• No chloride ion transport across cell membrane, mucus becomes too sticky, clogs airways and pancreatic ducts, causes symptoms
• Also interferes with sodium transport in the skin, so sweat test used to diagnose CF
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Chief Mechanisms: A Molecular Model• Associated with misfolded
CFTR protein: improper processing of Toll-like receptor 4 (TLR4) (Alton and Griesenbach)
• TLR4 responsible for inflammation
• Causes perpetually inflamed state in tissues, furthering the infection process (and the patient’s pain)
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Chief Mechanisms: Role of miRNAs
• Upregulated in CF cells• Controlled by
inflammatory processes under NF-kappa B• Increased IL-8
expression• Also disrupts SMAD3
growth factor signaling• SMAD3 proteins protect
against infections, hence, immunocompromisation
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Chief Mechanisms: A microbiological view• Pseudomonas aeruginosa
trapped by mucus• Mutation in CAV2 gene
• Caveolin proteins: lipid raft-mediated endocytosis, key role in inflammation, protein trafficking in epithelium
• CF patients: Caveolin 2/1 heterodimerization, co-localization with CFTR/P. aeruginosa
• Hence, earlier onset of infection
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Treatments: A World of Opportunities• No cure• Antibiotics, mucus
thinners, bronchodilators• Chest Physical therapy, to
help get mucus out and moving
• Specialized diets, enzymes
• Surgery, if symptoms get severe: Lung transplants
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Treatments: A World of Opportunities• Kalydeco – G551D mutation
– Vertex Pharmaceuticals – trials for other mutations underway
• Staff at Nationwide researching Kalydeco: • Chief: Karen McCoy
• Dr. Mitchell Drumm: Robotic screening of compounds for beneficial properties to be used in personalized medicine protocols
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Treatments: A World of Opportunities• Genomic medicine – Dr.
Ciaran Lee, University College Cork – Zinc Finger Nucleases and CRISPR/Cas9 proteins
• Broad Institute of Harvard and MIT: Sequencing of bacterial genomes from CF lung samples• Combat antibiotic
resistance
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AcknowledgementsThank you to:• Dr. Mitchell Drumm: for
his perspective on the work he has done with the discovery of the CFTR gene and with CF treatment
• The staff of Mechanisms: for giving me this opportunity to delve further into CF research.