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CRRAB II > Cystic Fibrosis > Flashcards

Cystic Fibrosis Flashcards

1
Q

Inheritance of CF?

A

Autosomal recessive

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2
Q

Gene involved in CF?

A

Cystic fibrosis transmembrane conductance regulator (CFTR) gene

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3
Q

What is the most freq. life-shortening genetic disease in US?

A

Cystic fibrosis

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4
Q

What is CFTR?

A

–Chloride and bicarbonate ion channel found on apical surfaces of epithelial cells

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5
Q

Structure of CFTR?

A
  • -12 membrane spanning domains that form pore for Cl- ion channel
  • -Nucleotide binding domains and R domain provide regulatory sites that promote channel opening
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6
Q

What is the primary cause of death in CF?

A

Respiratory failure in 90% of cases

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7
Q

Ave. survival w/CF?

A

37.4 yrs

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8
Q

Clinical consequences of CF?

A
  • -Respiratory failure
  • -Liver disease
  • -Pancreatic insufficiency
  • -CF diabetes
  • -Intestinal obstruction, malabsorption, CA
  • -Male infertility
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9
Q

Function of normal CFTR?

A
  • -When open HCO3- and Cl- flow in direction of EC gradient (out of cell)
  • -Controls luminal ion concentrations and PH
  • -Controls movement of H2O to apical surface of airway epithelial cell
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10
Q

What direction can CL- ions and H2O flow through CFTR channel?

A

Can only flow out if open

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11
Q

What is required for opening of channel?

A
  1. PKA phosphorylates R domain
  2. Two ATP bind NBD domains

PKA activated in response to cAMP

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12
Q

Apical export of Cl- by CFTR

A

1.CFTR is a chloride ion channel located on the apical surface of epithelial cells.
2.Export of Cl- into the lumen creates an osmotic gradient for the movement of water to the lumen mainly through a paracellular route.
3.CFTR is a channel so Cl- moves down the electrochemical gradient.
Basolateral channels and transporters create electrochemical conditions that favor export of Cl-.
Paracellular movement of Na+ prevents build up of negative charge that would create an unfavorable gradient.
4.ENaC counter acts and balances CFTR, pulls H20 in

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13
Q

Where is the CFTR gene found? How long is it?

A

Long arm of chromosome 7

250,000 bp

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14
Q

What ethnic group has the highest incidence of CF? The lowest?

A

Caucasian: highest

Asian-American: lowest

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15
Q

How many mutations have been identified?

A

> 1900

Only 5 mutations in 95% of cases

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16
Q

What does it mean for Tx with different CFTR mutations and incidence?

A
  • -Mutation based diagnostic tests feasible if tailored to ethnic group
  • -Molecular based therapies are feasible
17
Q

Mutation class 1

A
  • No protein produced. -Nonsense mutation creates stop codon. -Often mRNA degraded.
  • G542X, 5% of CF alleles
18
Q

Mutation class 2

A
  • Defective protein folding
  • Activates ER quality control
  • Degradation of protein
  • F508del, 70% of CF alleles
19
Q

Mutation class 3

A
  • Defective gating or regulation of channel opening

- G551D, 4% of CF alleles

20
Q

Mutation class 5

A

Normal CFTR produced, but decreased amounts

21
Q

Mutation class 4

A

Defective in ion transport

22
Q

Severe CFTR mutations

A

-Class 1, 2, 3

-

23
Q

Less severe CFTR mutations

A
  • Class 4, 5
  • About 5% of CFTR activity remaining
  • May have late presentation
  • Survival to 50 not uncommon
  • Pancreatic sufficient
24
Q

5 CFTR mutations

A
  1. F508del
  2. G542X
  3. G551D
  4. W1282X
  5. N1303K

All in severe category

25
Q

F508del

A
  • -Most common CFTR mutation
  • -Almost complete loss of functional proteins
  • -Folding defect leads to degradation of most
  • -Small fraction of protein at cell surface defective in gating and stability
26
Q

Synthesis of CFTR protein

A
  • -In ER
  • -Needs inta-domain folding and inter-domain interactions
  • -Needs interaction w/series of chaperones
27
Q

What does the F508del result in?

A
  • -Incorrect folding of NBD1 domain where it is location and incorrect interaction of NBD1 w/other domains.
  • -Altered interaction with chaperones
  • -Retention in ER and activation quality control pathways
  • -Degradation by proteosome
28
Q

Does mutation class predict the severity of disease in individuals?

A

No. Those classified as severe are there because they cause defects in pancreatic ducts, tend to have worse pulmonary disease. Other factors influence outcome

29
Q

Are severe mutations sufficient for development of CF-related diabetes and liver disease?

A

No. The mutations are necessary, but not sufficient.

30
Q

Why does inactivation of CFTR affect respiratory function?

A
  • Loss of luminal H2O and ion balance
  • -HCO3- required for expansion of mucin after secretion, if absent, cilia can’t move properly and clear bacteria
  • -Inflammation
31
Q

How does inflammation affect respiratory function?

A
  1. Decreased ASL, ineffective mucin barrier failure to clear bacteria
  2. Inflammatory pathways activated (LPS > TLR4 > MyD88 > NFkB)
  3. Increased mucin secretion (ineffective)
  4. Inflammatory mediators (TNF-a, IL-8) recruit neutrophils
  5. Neutrophils release elastase, damage CFTR and epithelial cell DAMPs further stimulate inflammatory signaling.
32
Q

Path of respiratory failure

A
  1. Decreased ASL layer –> builds up viscous mucus –> fail to clear bacteria
  2. Persistent colonization and desicated mucus –> inflammation
  3. Infection, inflammation and mucus plugging –> long-term structural damage
  4. respiratory failure
33
Q

What is the primary thing that must be known when considering what causes chronic airway infection and permanent damage?

A

Decreased ASL layer

34
Q

What is the cause of death for most ind. w/ CHF?

A

Pulmonary failure

35
Q

Major organisms involved in infection

A 
H. influenzae
Staph aureus
Pseudomonas aeruginosa
MRSA
Burkholderia cepacia
36
Q

Tx mainstays to try and prevent pulmonary damage

A
  1. Chest physiotherapy to improve drainage
  2. Aggressive rx of infection w/antibiotics
  3. Hypertonic saline and DNase aerosols to make mucus less viscous
  4. Anti-inflammatories

CRRAB II (13 decks)

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