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Mucosal Surfaces > L28- Cf 2 > Flashcards

L28- Cf 2 Flashcards

1
Q

How many are carriers for CFTR mutation

A

1 in 25

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2
Q

What does CFTR mean

A

Cf transmembrane conductance regulatory

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3
Q

What does 7q31.2 mean

A

CFTR is on chr 7, long P arm, at region 3, band 1 and subband 2

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4
Q

How long is it

A

189kb and 1480 aa

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5
Q

What % of mutations are missense (change in aa)

A

40%

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6
Q

What is the most common mutation and what class is it

A

Phe508 deletion which is a class 2 because it doesn’t get trafficked from er to the membrane due to incorrect folding

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7
Q

What % are the gly551asp mutation

A

3% (glycine change to aspartic acid)

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8
Q

What type of class is this

A

Class 3 because it gets trafficked to the membrane but reduced channel opening and gating activity

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9
Q

What is class 1 and what’s it caused by

A

No mrna or protein produced due to premature stop codon or splicing defects

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10
Q

What is class 2

A

Proteins not trafficked to membrnae

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11
Q

What is class 3 and 4

A

gating issues for class 3 and class 4 is issues / alteration in conductance

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12
Q

What are the rare class 5 and 6 mutations

A

Less CFTR protein is produced and class 6 is abnormally high turnover of CFTR on cell membrane

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13
Q

What secondary messenger activates the CFTR anion channel

A

Camp via pka phos activation of CFTR

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14
Q

What is CFTR gated by

A

Atp gated

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15
Q

What conductance does it usually cause

A

Cl conductance but can also be thiocyanate and hco

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16
Q

What are the 5 domains

A

2 membrane spinning domains (pore forming MSD)

2 nucleotide binding domains NBD(atp binding and hydrolysis)

1 regulatory R domain (what gets phos by pka)

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17
Q

What is atp and phosphorylation needed for (Shepard and Walsh 1999)

A

Needed for channel activation, gating activity channel opening or closing via hydrolysis

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18
Q

Which article discusses why phe508 doesn’t get trafficked to membrane

A

Scott- ward 2009

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19
Q

What recognises the mutation and targets it for proteasomes deg

A

Er quality control system erqc

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20
Q

What binds to the phe508 mutation and allows erqc recognition

A

Hsp70

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21
Q

Which domain does phe508 occur in same as gly551asp

A

Nbd1

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22
Q

How does the gly change to asp affect gating as a class 3 mutation

A

Occurs in one of the atp binding sites so atp can’t bind and affects gating activity (sheppard and Walsh 1999)

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23
Q

Which other channels other than enac does CFTR regulate

A

Cl channels eg ORCC, CaCC (outward rectifying)
K channels
Anion exchanger SLC26 family

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24
Q

Through what domain of CFTR do some have direct interaction

A

PDZ domain

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25
Q

Is CFTR expressed evenly on all epi cells

A

No. Expressed on ionocytes a lot more which is a therapeutic target

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26
Q

Which article talks about other channels and the asl homeostasis

A

Haq et Al 2015

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27
Q

Which 3 channels are important for asl homeostasis which are all modulated by CFTR

A

CaCC, slc26a, enac

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28
Q

What are the 2 layers of asl

A

Periciliary layer pcl which is kept water for cilia movement

Then gel-mucin made mucus on top

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29
Q

In normal airways not cf, which protein regulates enac so no na hyper absorption

A

Splunc1

30
Q

Which conditions is this lost in

A

Low ph/acidic ph eg when CFTR doesn’t work

31
Q

What does water leaving the pcl mean

A

Compression of the ciliary layer as mucus builds up

32
Q

What does slc26a do for homeostasis

A

Uses the Cl/HCO exchanger it has to secrete HCO for ph regulation therefore increasing splunc1 action and maintains bacterial barrier

33
Q

Which article discusses in copd lectures suggested which things cause mucus hypersecretion in cf too

A

Kim 2013

Th2,th17, infections, NE, oxidative stress

34
Q

How does mucus actually increase

A

Goblet cell hyperplasia and submucosal gland hypertrophy

35
Q

Which 4 effects does acidification in cf cause

A

Mucus misfolding/ viscosity

Amp/antimicrobial impaired

reduced sphingipid metabolism

Reduced control of ion transport (splunc 1)

36
Q

Which spingolipud accumulates in cf due to the ph affecting metabolism enzymes (brodlie et Al 2010)

A

Ceramide (

37
Q

What does ceramide accumulation do (brodlie 2010)

A

Increases chronic inflammation through death of airway epi cells, proinflam cytokines and susceptibility to pa

38
Q

Which infections seen in younger cf patients

A

S aureus mainly but also hinfleunzae

Pa is in older

39
Q

What % does mrsa affect in cf which is more virulent as methicillin resistant

A

5-15%

40
Q

What sorts of things can if sa is pathogenic do

A

Damage to epi cells, inflammation and infiltration of other pathognes

41
Q

When is fev1 worse than just if cf have sa alone (schwerdt et Al 2018)

A

If co colonised with pa so could be synergistic

42
Q

When is sa most common in cf (schwerdt 2018)

A

7-19years (schwerdt 2018)

43
Q

Which article discusses more saureus and airway epi cells

A

Silva 2004

44
Q

Which antimicrobial things needed to fight saureus

A

Lysozymes, lactoferrins, slpI

45
Q

How can saureus induce apoptosis and necrosis in epi cells causing more inflammation and damage

A

Has an a-toxin which forms pores in membrane by cleaving phospholipids

46
Q

Which pathways of inflammation can saureus and pa induce

A

Nfkb and il8

47
Q

Which article discusses cf, pa and inflammation

A

Hart 2002

48
Q

Which th response does pa trigger which was linked to mucus hypersecretion in Kim 2013

A

Th2

49
Q

Why would the f508 deletion reduce clearance of pa

A

Because usually internalised through the cf and then cleared in the cell

50
Q

Which exo polysaccharides do pa produce which can block neutrophil protection

A

Alginate

51
Q

Which process of signalling allows pa to produce biofilms and also alginate (virulence)

A

Quorum sensing

52
Q

What do they release which causes damage to airway and low fev1

A

Proteases, elastases, lipases

53
Q

Which liquid in lungs do they reduce causing collapse

A

Surfactant

54
Q

How do they increase during inflammation/ chronic inflammation (malhotra 2019)

A

Aea nitrates which build up during inflammation

55
Q

Which bacteria is harder to treat than pa and saureus

A

Non tuberculous mycobacterium

56
Q

Why would someone with ntm not have a transplant

A

Cannot be immunosuppressed as ntm severely reduces lung function

57
Q

Which types of remodelling can neutrophilic inflammation cause

A

Bronchitis and bronchiectasis in cf (progressive and persistent inflammation)

58
Q

Other than neutrophils what else is seen in cf inflammation and remodelling

A

TNFa, il 1b, il17, il6, il8

59
Q

What % of wbc are neutrophils

A

60%

60
Q

Other than hyperplasia of goblet cells why other remodelling occurs in cf

A

Thickening of reticular basement membrane and smooth muscle of airway due to hyperplasia

61
Q

What is the reticular basement membrane

A

The layer under epi cells before the submucosa begins then smooth muscle

62
Q

Which cytokines associated with cf can cause basal cell hyperplasia (thick bm) (adam et Al 2015)

A

Il1b, il6, tnfa

63
Q

Which part of pa can cause goblet cell hyperplasia

A

Lps

64
Q

What are Ali cell cultures

A

Airway liquid interface cultures

Samples from nose of lower airways via a brush sample taken to study airways of cf

65
Q

Which equipment is used to measure ion transport/ study channels in the Ali cultures

A

Ussing chamber

66
Q

Why is a gradient present / polarised cells in epi cells

A

Polarised between the apical and baso lateral site

67
Q

What activates CFTR electrical movement in ussing chamber if functional

A

Foreskolin

68
Q

What would happen if a CFTR inhibitor added if functional

A

Massive drop in electrical movement

69
Q

How is this different to if not functional eg Cf patients

A

No electrical movement change when foreskolin or the inhibitor added through CFTR

70
Q

Which Cl channel works for both cf and non cf seen when utp added to ussing chamber showing potential therapy

A

Tmem16a

Mucosal Surfaces (33 decks)

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