1. 2015-11-15Science of Life CNU1

2. Many serious genetic diseases can be traced to ion channel mutations in the gene encoding protein 2015-11-15Science of Life CNU2

3. 2015-11-15Science of Life CNU3

4.  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. 2015-11-15Science of Life CNU4

5.  Cystic fibrosis is a chronic, progressive, hereditary disease, exocrine glands, is the most common Caucasian shortened life expectancy will cause the genetic disease. 2015-11-15Science of Life CNU5

6.  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. 2015-11-15Science of Life CNU6

7.  Airway glands produce thick, thick secretions, airway obstruction, and cause pulmonary infection 2015-11-15Science of Life CNU7

8.  When the pulmonary alveolar collapse, the pneumonia will often follow. Pneumonia in cystic fibrosis patients is the most susceptible, and easy to recurrent infections. 2015-11-15Science of Life CNU8

9. 2015-11-15Science of Life CNU9

10.  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 2015-11-15Science of Life CNU10

11.  Cystic fibrosis gene was isolated in 1989, treatment of the disease has entered a new era! 2015-11-15Science of Life CNU11

12.  The cystic fibrosis transmembrane conductance regulator(CFTR) is a chloride channel located in the apical membrane of many epithelial cells. 2015-11-15Science of Life CNU12

13. 2015-11-15Science of Life CNU13

14. Structure Research of CFTR Gating of CFTR channels Gating studies before crystallization Crystallographic studies of ABC transporters Gating studies after crystallization 2015-11-15Science of Life CNU14

15. Gating of CFTR channels  The first piece of evidence for CFTR being an ATP-gated ion channel comes from patch-clamp experiments by Anderson 2015-11-15Science of Life CNU15

16.  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 ATPγS. 2015-11-15Science of Life CNU16

17.  The first piece of evidence for CFTR being an ATP-gated ion channel comes from patch-clamp experiments by Anderson 2015-11-15Science of Life CNU17

18.  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. 2015-11-15Science of Life CNU18

19. Crystallographic studies of ABC transporters 2015-11-15Science of Life CNU19

20. Gating studies after crystallization 2015-11-15Science of Life CNU20

21. 2015-11-15Science of Life CNU21

22. 2015-11-15Science of Life CNU22

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

24. 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

25. 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.

26. 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.

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

28. Bacterium adheres poorly to the wall of an intestine Typhoid fever

29. Antibiotics Bronchodilator Mucus solvent Antioxidant Gene therapy Five types of drugs

30. 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.

31. 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.

32. 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

33. To date, none of the clinical trials of gene therapy has resulted in significant improvement of either physiologic processes or disease symptoms.

35. Natural Compound: Theophylline Curcumin

43. Denufosol Tetrasodium