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Many serious genetic diseases can be traced to ion channel

mutations in the gene encoding protein

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Most diseases are because some of these cells to produce and transmit impulses capacity is reduced - excitable cells (eg, muscle cells, nerve cells and sensory cells) affected the membrane ion permeability

Compared with other diseases, cystic fibrosis (CF) is the most common epithelial cells by acting on ion channel defects caused by disease, but also the most thoroughly studied diseases.

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Cystic fibrosis is a chronic, progressive, hereditary disease, exocrine glands, is the most common Caucasian shortened life expectancy will cause the genetic disease.

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The disease of the defective gene will cause the body to produce excessive mucus, especially on the respiratory system and digestive tract of the impact of the drama.

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Airway glands produce thick, thick secretions, airway obstruction, and cause pulmonary infection

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When the pulmonary alveolar collapse, the pneumonia will often follow. Pneumonia in cystic fibrosis patients is the most susceptible, and easy to recurrent infections.

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In Scandinavia, there is an average of 25 individuals carrying one of a cystic fibrosis can be copied from the gene. because they do not show the phenotype of mutant genes, so most will not find that heterozygous carriers of them. Therefore, This white group, there are about 1 / 2500 of the infant is homozygous recessive, which are born with cystic fibrosis.Usually the children suffering from cystic fibrosis call their disease will be the "65 Roses", because the English pronunciation in the Sixty-five roses and Cystic fibrosis is very close to

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Cystic fibrosis gene was isolated in 1989, treatment of the disease has entered a new era!

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The cystic fibrosis transmembrane conductance regulator(CFTR) is a chloride channel located in the apical membrane of many epithelial cells.

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Gating of CFTR channels

The first piece of evidence for CFTR being an ATP-gated ion channel comes from patch-clamp experiments by Anderson

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The role of ATP hydrolysis in CFTR gating was implied by Anderson’s studies since the CFTR channel failed to open in the presence of nonhydrolyzable ATP analogs such as AMP-PNP or ATP S.γ

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The first piece of evidence for CFTR being an ATP-gated ion channel comes from patch-clamp experiments by Anderson

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In addition to nonhydrolyzable ATP analogs, ADP was the other commonly used nucleotide for CFTR gating studies. Anderson et al.[9] showed that ADP by itself cannot stimulate the channel activity, but in the presence of ATP it inhibits CFTR activity.

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Crystallographic studies of ABC transporters

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Gating studies after crystallization

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An explanation for the debilitating effects on lung function from the absence of the CFTR protein.

More than 1000 different mutations

70% of the alleles contain the same genetic alteration

All missing 3bp of DNA that encode a phenylalanine at position 508

Fail to be processed normally within the membrances of the endoplasmic reticulum

Can not reach the surface of epithelial cells

At lower temperature, it functions quite well.

small molecules that can bind to these mutant CFTR molecules, preventing destruction , reach the cell surface.

Several promising candidates have been identified, but none has yet to be proven effective in clinical trials.

The ΔF508 mutation had to have originated more than 50,000 years ago to have reached such a high frequency.

Heterozygotes may receive some selective advantage.

No record of cholera epidemics in Europe until the 1820s.

Cholera

Bacterium adheres poorly to the wall of an intestine

Typhoid fever

Antibiotics

Bronchodilator

Mucus solvent

Antioxidant

Gene therapy

Five types of drugs

gene therapy—replacement of the defective gene with normal

Cystic fibrosis is a good candidate for gene therapy

because the worst symptoms of the disease result from the defective activities of epithelial cells that line the airways are accessible to agents that can be delivered by inhalation of an aerosol.

delivery systems:

one group of trials: the normal CFTR gene was incorporated into the DNA of a defective adenovirus. The recombinant virus infect the cells of the airway, delivering the normal gene to the genetically deficient cells.

disadvantage the viral DNA does not become integrated into host cell induces an immune response eliminates the virus and leads to lung inflammation.

for fear of initiating the formation of cancers.

In other trials: the DNA encoding the normal CFTR gene has been linked to positively charged liposomes that can fuse with the plasma membranes of the airway cells, delivering their DNA contents into the cytoplasm. advantage less likely to stimulate a destructive immune response

disadvantage less effective in modification

To date, none of the clinical trials of genetherapy has resulted in significant improvement of either physiologicprocesses or disease symptoms.

Natural Compound:

Theophylline

Curcumin

Denufosol Tetrasodium