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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
CFTR and ENaC _____
INTERACT CFTR is a regulator of ENaC
26
CFTR is a regulator of ENaC what does that mean for the case of CF
In CF reduced inhibition of ENaC (seems to be gain of function) Reduced Cl secretion AND enhanced Na absorption
27
Alveolar cell model
APICAL ENaC - Na reabsorption CF - CL REABSORPTION BASAL KCl cotransporter Na/K ATPase K channel
28
Why is Cl reabsorbed in the Alveolar cells
Because KCl cotransporter on the basolateral membrane - sets up a low IC Cl driving Cl reabsrption across the apical membrane
29
In alveolar cells how does CFTR interact with ENaC
CFTR ACTIVATES ENaC
30
Why is the height of the ASL important in the alveolar cells
Has to be optimum for gas exchange to occur
31
What is the effect of CF on the alveolar cells of the lungs
Oedema - fluid in the lungs
32
Cell model: Distal Sweat Gland
APICAL ENaC (Na IN) CFTR (Cl IN) BASAL Na/K ATPase CFTR (ALSO ON BASAL SIDE) K Channel (OUT)
33
Describe the formation of Sweat in the distal sweat glands
CFTR independent secretion of CL into the lumen of the sweat gland Absorption of Na and Cl from the lumen Water follows
34
Describe why CF patients have salty sweat
Failure to get Cl absorption from the sweat | ENaC not activated
35
What is the interaction between CFTR and ENaC in the distal sweat gland
CFTR ACTIVATES ENAC
36
What are the driving forces seen in the distal sweat gland
One for Cl to move through cFTR on the apical membrane | ANOTHER one for Cl to move across the basolateral membrane through CFTR
37
Why is antibiotic resistance common in CF sufferers
Suffer from frequent infections
38
What do all of the CF treatments have in common
All of them treat the symptoms
39
Ivacaftor is a
Potentiator
40
Lumacaftor is a
Corrector
41
Elexacator is a
Corrector
42
Tezacaftor is a
Corrector
43
Orkambi contains
Ivacaftor and lumacaftor
44
Ivacaftor alone used to treat
G551D
45
Orkambi used to treat
F508 homozygotes
46
What is a potentiator used for
To increase the Po | Used to treat gating mutations
47
What is a corrector used for
Traffic the mutant protein to the membrane and increase the N number
48
What was the intial step in vertex pharmaceeticals to find CF drigs
100'000 drugs were screened
49
FIRST CLINICAL TRIAL FROM LECTURE
Vx-770/Ivacaftor for a G551D mutant
50
What is forskolin added for
Stimulate CFTR | Stimulation of PKA - phosphorylation of CFTR
51
What is the effect on SCC in G551D of FSK
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
What is the effect of VX-770 (lumacaftor) on the ISC of G551D cells
Increase above WT unstimulated in the presence of FSK
53
Describe the trace seen when adding FSK, VX-770 then CFTR inhibitor to the G551D cells What was performed after this?
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
What is the function of single channel recordings
Investigate Po
55
Descibe what seen in the single channel recordings for patients with G551D
In mutant not as many channel opening - less frequent
56
What was seen in the single channel recordings when the cells were exposed to ivacaftor
Many more deflections seen - increase in Po Recovery?
57
When looking at short circuit currents from CFTRwhy add amiloride
ENaC would contaminate the recordings
58
Describe what was seen in the short circuit recordings when ivacaftor added
Increase in current which increases as the concentration of ivacaftor is increased
59
Describe the experimental conditions when looking at the effect of ivacaftor of the ASL Describe the results seen
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
Describe the experimental conditions used to look at the effect of ivacaftor on the cililary beat frequency What were the results seen
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
CBF
Ciliary beat frequncy
62
Ivacaftor clinical trials were
Randomised, double blind clinical trials
63
Ivacaftor clinical trials stats
Sufferers with at least the 1 G551D mutation | Lasted 48 weeks
64
What was the doseing protocol for the ivacaftor trials
150mg every 12 hours
65
How was change in FEV1 value expressed in the ivacaftor clinical trial data
AS CHANGE OF % PREDICTED | Positive value - closer to predicted and this is good
66
Describe the effect of ivacaftor on lung function
Within two weeks 10% imporvement
67
Describe the effect of ivacaftor on the number of pulmonary exacerbation events
Decrease in the proportion of the number of subjects who had an event of pulmonary exacerbation
68
Describe the effect of ivacaftor on sweat NaCl
When taking ivacaftor sweat Cl drops BELOW THE CLINICAL TRESHOLD
69
Describe the effect of ivacaftor on nasal potential difference
Increase in the concentration of ivacafor lead to an improvement of change in the baseline nasal epitheliun
70
What is the effect of using isoproterenol
It is a beta agonist | Which activates CFTR through cAMP

BMS346 - Epithelial Physiology (10 decks)

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