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BMS346 - Epithelial Physiology > L4 CF and Small Molecules (Part 1) > Flashcards

L4 CF and Small Molecules (Part 1) Flashcards

1
Q

How many TMD CFTR

A

12 - 2 groups of six

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2
Q

What are the important regions of the CFTR protein?

A

R domain - where phosphorylation occurs

NBD1/2 where nucelotides are able to bind

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3
Q

Describe the pattern of mutations if CFTR

A

No obvious pattern

NBDs are common places for mutations to be observed

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4
Q

What is a common mutation

A

F508

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5
Q

How many mutations have the potential to cause CF

A

over 1200

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6
Q

Describe a type 1 mutation

A

Null production

mRNA is unstable and no CFTR is made

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7
Q

Describe a type 2 mutation

A

Trafficking

CFTR is made but not trafficked effectively to the membrane

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8
Q

Example of a type 2 mutation

A

F508 example

Misfolding leads to degradation

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9
Q

Describe a type 3 mutation

A

Regulation
Protein is made and gets to the membrane but is not regulated properly e.g. protein doesnt respond to phosphorylation or is unable to be phosphorylated

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10
Q

Describe a type 4 mutation

A

Gating

Channels don’t open effectively - Po is lower

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11
Q

Describe a type 5 mutation

A

Partial reduction in mRNA

Some mRNA is present so some is made but this is reduced - reduction in the ammount present in the apical membrane

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12
Q

Describe a type 6 mutation

A

High turnover of CFTR

Ammount of time CFTR spends in the apical membrrane is reduced

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13
Q

Example of a type 6 mutation

A

F508 - remoced equikcly from the membrane

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14
Q

What is the normal level for sweat chloride

A

20mmol

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15
Q

What is the diagnostic threshod for sweat chloride

A

60mmol

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16
Q

What classes of mutations are very serious leading to a sweat chloride in excess of 100mmol

A

Classes 1-3

Correlated with a massive loss of function in CFTR

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17
Q

What do class 4-5 mutations tend to be associated with?

A

Pancreatic insufficiency - failure to secrete digestive enzymes

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18
Q

for the less severe mutations that dont cause diagnostic threshold to be exceeded what tests could be used

A

Nasal potential difference

Biopsy from the gut - test the response of this to ACh

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19
Q

Do you need 100% function for normal function

A

No

Carriers asymptomatic with 50% of the protein produced

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20
Q

Where is the f508 mutation found

A

NBD1

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21
Q

What is the minimum ammount of functional CFTR required for normal function

A

15%

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22
Q

Describe the channels seen in the upper airway cell

A

APICAL
ENaC - Na into the cell
CFTR - Cl secretion

BASAL
Na/K ATPase
NKCC1 (Na 2Cl and K all IN)
K+ channels

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23
Q

What is the effect of activation of CFTR on ENaC

A

CFTR inhibits mucous

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24
Q

Effect on Non functional CFTR

A

ASL drops - PCL drops
Muco-ciliary clearance is slowed
Thick mucous with bacteria and viruses

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25
Q

CFTR and ENaC _____

A

INTERACT

CFTR is a regulator of ENaC

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26
Q

CFTR is a regulator of ENaC what does that mean for the case of CF

A

In CF reduced inhibition of ENaC (seems to be gain of function)
Reduced Cl secretion AND enhanced Na absorption

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27
Q

Alveolar cell model

A

APICAL
ENaC - Na reabsorption
CF - CL REABSORPTION

BASAL
KCl cotransporter
Na/K ATPase
K channel

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28
Q

Why is Cl reabsorbed in the Alveolar cells

A

Because KCl cotransporter on the basolateral membrane - sets up a low IC Cl driving Cl reabsrption across the apical membrane

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29
Q

In alveolar cells how does CFTR interact with ENaC

A

CFTR ACTIVATES ENaC

30
Q

Why is the height of the ASL important in the alveolar cells

A

Has to be optimum for gas exchange to occur

31
Q

What is the effect of CF on the alveolar cells of the lungs

A

Oedema - fluid in the lungs

32
Q

Cell model: Distal Sweat Gland

A

APICAL
ENaC (Na IN)
CFTR (Cl IN)

BASAL
Na/K ATPase
CFTR (ALSO ON BASAL SIDE)
K Channel (OUT)

33
Q

Describe the formation of Sweat in the distal sweat glands

A

CFTR independent secretion of CL into the lumen of the sweat gland
Absorption of Na and Cl from the lumen
Water follows

34
Q

Describe why CF patients have salty sweat

A

Failure to get Cl absorption from the sweat

ENaC not activated

35
Q

What is the interaction between CFTR and ENaC in the distal sweat gland

A

CFTR ACTIVATES ENAC

36
Q

What are the driving forces seen in the distal sweat gland

A

One for Cl to move through cFTR on the apical membrane

ANOTHER one for Cl to move across the basolateral membrane through CFTR

37
Q

Why is antibiotic resistance common in CF sufferers

A

Suffer from frequent infections

38
Q

What do all of the CF treatments have in common

A

All of them treat the symptoms

39
Q

Ivacaftor is a

A

Potentiator

40
Q

Lumacaftor is a

A

Corrector

41
Q

Elexacator is a

A

Corrector

42
Q

Tezacaftor is a

A

Corrector

43
Q

Orkambi contains

A

Ivacaftor and lumacaftor

44
Q

Ivacaftor alone used to treat

A

G551D

45
Q

Orkambi used to treat

A

F508 homozygotes

46
Q

What is a potentiator used for

A

To increase the Po

Used to treat gating mutations

47
Q

What is a corrector used for

A

Traffic the mutant protein to the membrane and increase the N number

48
Q

What was the intial step in vertex pharmaceeticals to find CF drigs

A

100’000 drugs were screened

49
Q

FIRST CLINICAL TRIAL FROM LECTURE

A

Vx-770/Ivacaftor for a G551D mutant

50
Q

What is forskolin added for

A

Stimulate CFTR

Stimulation of PKA - phosphorylation of CFTR

51
Q

What is the effect on SCC in G551D of FSK

A

Unstimulated WT has a basical level which is heavily increased by presence of FSK
In G551D initial level much lower, less of an increase in presence of FSK

52
Q

What is the effect of VX-770 (lumacaftor) on the ISC of G551D cells

A

Increase above WT unstimulated in the presence of FSK

53
Q

Describe the trace seen when adding FSK, VX-770 then CFTR inhibitor to the G551D cells

What was performed after this?

A

Add FSk, small increase, add VX-770 = masive increase, removed when CFTR inhibitor is applied

Performed in a different order - VX-770, FSK and CFTRinhibotor

54
Q

What is the function of single channel recordings

A

Investigate Po

55
Q

Descibe what seen in the single channel recordings for patients with G551D

A

In mutant not as many channel opening - less frequent

56
Q

What was seen in the single channel recordings when the cells were exposed to ivacaftor

A

Many more deflections seen - increase in Po

Recovery?

57
Q

When looking at short circuit currents from CFTRwhy add amiloride

A

ENaC would contaminate the recordings

58
Q

Describe what was seen in the short circuit recordings when ivacaftor added

A

Increase in current which increases as the concentration of ivacaftor is increased

59
Q

Describe the experimental conditions when looking at the effect of ivacaftor of the ASL

Describe the results seen

A

ASL starts very high and then drops to optimum level
VIP added - stimulates PK-A –> CFTR

G551D alone with VIP - ASL falls way too low

With ivacaftor present height is shifted closer to the height of the wildtype

60
Q

Describe the experimental conditions used to look at the effect of ivacaftor on the cililary beat frequency

What were the results seen

A

DMSO used as a control - VIP added

Without any VX-770 CBF was very low

Vx770 increased the CBF but with VIP and VX770 the CBF was brought closest to the wild type levels

61
Q

CBF

A

Ciliary beat frequncy

62
Q

Ivacaftor clinical trials were

A

Randomised, double blind clinical trials

63
Q

Ivacaftor clinical trials stats

A

Sufferers with at least the 1 G551D mutation

Lasted 48 weeks

64
Q

What was the doseing protocol for the ivacaftor trials

A

150mg every 12 hours

65
Q

How was change in FEV1 value expressed in the ivacaftor clinical trial data

A

AS CHANGE OF % PREDICTED

Positive value - closer to predicted and this is good

66
Q

Describe the effect of ivacaftor on lung function

A

Within two weeks 10% imporvement

67
Q

Describe the effect of ivacaftor on the number of pulmonary exacerbation events

A

Decrease in the proportion of the number of subjects who had an event of pulmonary exacerbation

68
Q

Describe the effect of ivacaftor on sweat NaCl

A

When taking ivacaftor sweat Cl drops BELOW THE CLINICAL TRESHOLD

69
Q

Describe the effect of ivacaftor on nasal potential difference

A

Increase in the concentration of ivacafor lead to an improvement of change in the baseline nasal epitheliun

70
Q

What is the effect of using isoproterenol

A

It is a beta agonist

Which activates CFTR through cAMP

BMS346 - Epithelial Physiology (10 decks)

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