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BMS242 CVS Phys > L7 - Respiratory Channelopathies > Flashcards

L7 - Respiratory Channelopathies Flashcards

1
Q

Give an example of a respiratory channelopathy

A

Cystic fibrosis

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2
Q

CF inheritance pattern

A

Autsomal recessive

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3
Q

What is the main effect of CF

A

Alters electrolyte transport

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4
Q

How many born with

A

1 in 2500

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5
Q

How many are carriers

A

1 in 20

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6
Q

Describe the effect on the airways

A

Clogging and infections

Increased incidence of persistent respiratory tract infections – symptoms multiplied

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7
Q

How many experience airway effects `

A

Mostly all

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8
Q

Effects on the liver

A

Blockages of the small bile ducts

Liver function problems

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9
Q

How many experience liver effects

A

Around 5%

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10
Q

Effects on the pancreas

A

Blockages of the ducts

Prevention of the secretion of digestive enzymes: prevents digestion of food - lack of weight being put on

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11
Q

How many experience pancreas effects

A

Around 65%

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12
Q

Effects on the small intestine

A

Obstruction due to thick contents - operation required for removal - then expect episodes during the life

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13
Q

What percentage of newborn CF require an operation on the small intestine

A

10%

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14
Q

Effects on the reproductive tract

A

Infertility in males due to absence of the Vas Deferens

Small number of issues in women

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15
Q

How many male CF sufferers are infertile

A

95%

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16
Q

Effect of CF on the skin

A

Excess secretion of NaCl through the sweat galnds

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17
Q

What is the name for small intestine obstruction

A

Meconium Ileus

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18
Q

How many faulty copies of the gene required for disease phenotype

A

2

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19
Q

How much protein do the carriers produce

A

1/2

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20
Q

Is half the ammount of CFTR sufficient for normal phys function

A

Yes

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21
Q

CFTR is a ___ channel

A

Cl-

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22
Q

Direction of the CFTR depends on

A

The cell type

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23
Q

What does NBD stand for

A

Nucelotide binding domain

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24
Q

How many NBDs

A

2

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25
Q

What binds to the NBDs

A

ATP

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26
Q

What are the NBDs involved in

A

Regulation

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27
Q

How many CFTR transmembrane domains

A

12

28
Q

What is the regulatory domain

A

A phosphorylation site where the ATP is hydrolysed

29
Q

How many mutations are capable of causing CF

A

1900

30
Q

70% of mutations are

A

Delta F508

31
Q

Where is the Delta F508 mutation

A

NBD1

32
Q

What does ‘variable penetrance’ mean

A

Genetic (non-coding) DNA and eviromental affects change the severity of the disease

33
Q

Describe one environmental factor which may result in variable pentetrance

A

Socioeconomic

Likelyhood to take medication

34
Q

Describe the effect a mutation would have on production

A

Protein not made

35
Q

Describe the effect a mutation would have on processing

A

Protein is missfolded and subsequently degraded

36
Q

Describe the effect a mutation would have on trafficking

A

Protein doesnt get to the membrane

37
Q

Describe the effect a mutation would have on regulation

A

In NBD1/2 and R region

Channel doesnt open

38
Q

Describe the effect a mutation would have on conduction

A

Makes it to the membrane but doesnt open

39
Q

What is the most common mutation for CF

A

Delta F508

40
Q

What is the allelic frequency of delta F508

A

90%

41
Q

Name other mutations with a 1-3% allelic frequency

A

G551D
W1282X
GS43X
N1303K

42
Q

What mutation has an unusually high allelic frequency of 30% in the UK

A

G551D

43
Q

Describe the pathology of CF in the lung

A 
Viscous airway mucous 
Recurrent bacterial infections 
Antibiotic resistance 
Inflammation 
Tissue degeneration ultimaetly leading to death
44
Q

Why might CF patients show a.biotic resistance

A

May/recurrent infections –> treated with antibiotics –> development of resistance

45
Q

Two channels on the apical side of the membrane of the airway cell

A

ENaC and CFTR

46
Q

Three channels on the basolateral side of the airway cell membrane

A

Na/K ATPase
NKCC1
K+ channel

47
Q

Describe the normal airway cell model

A

Na/K ATPase sets up a low IC Na
Causes influx for Na through NKCC1 - along with K and 2 Cl
K recycled through basolateral membrane
Cl leaves through CFTR channel on the apical membrane
Normal function of CFTR to inhibit ENaC
This keeps air-fluid layer high enoguh (7 um) to keep cilia covered and allow them to beat

48
Q

Describe the airway cell model for CF sufferers

A

Na/K ATPase sets up a low IC Na
Causes influx for Na through NKCC1 - along with K and 2 Cl
K recycled through basolateral membrane
CFTR not present ENaC is not inhibited
Water drawn in causing thickness of air-fluid layer to decrease
Cilia unable to beat, and fold over

49
Q

What is the evidence from bronchial cell cultures

A

Both started with an abnormally high air fluid layer
Control can regulate thickness of layer to 7 um
Experimental (CF -/-) cant regulate and air fluid layer falls very low

50
Q

In the deltaF508 mutation what is normal

A

Production, conduction and regulation

51
Q

What is abnormal about the protein in a delat F508 mutation

A

It misfolds so is degraded and doesn’t make it the membrane

52
Q

What would happen if the delta F508 mutant protein made it to the membrane

A

It would almost function normally

53
Q

Describe why allelic frequency for CFTR is so high

A

CFTR present on colonic crypt cells
When bacterial infection, bact produce enterotoxins, these then act of CFTR causing excess Cl secretion so excess water in the faeces –> cholera/diahhorrea
In carriers only half the amount of CFTR protein, so less Cl and H20 in the faeces ==> more likely to survive a cholera infection

54
Q

List some of the current treatments for CF

A 
Physiotherapy 
Antibiotics 
Mucolytics (Dnase) break down mucous 
Bronchodilator
Steroids
55
Q

Describe how gene therapy for CF may work

A

Deliver CFTR DNA to the cells
DNA then transcribed
Functional CFTR protein produced

56
Q

Which cells would be easiest to target with gene therapy

A

The lungs

57
Q

Issues with gene therapy to treat CF

A

Challenging - how would you deliver the genes to other cells of the body
Expensive
Poor success rate

58
Q

Describe how a read through agent would work

A

Force production of the full length protein when there may be premature stop codons or nonsense mutations

59
Q

Example of a read through agen

A

Aminoglycoside antibiotics

e.g. gentamycin

60
Q

Decribe how correctors would work

A

Force mutant CFTR to the membrane - if it is functional then normal phys restored

61
Q

Example of a mutation where a corrector would work

A

Delta F508

62
Q

Describe how a potentiator would work

A

Increase the open prob, of the CFTR (these must have been trafficked to the membrane)

63
Q

Example of a potentiator

A

Ivacaftor VX-770

64
Q

What mutation does Ivacaftor target

A

G551D

65
Q

What combination of drugs would be good for a delta F508 mutation

A

Potentiators and correctors

66
Q

Describe the results of the Ivacaftor clinical trials

A

Increase in thickness of the fluid layer
Increase in the absolute change in FEV1%
Proportion of event-free subjects was higher than in the placebo groups
Sweat Cl conc fall to below the clinical threshold

BMS242 CVS Phys (12 decks)

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