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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.