Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

PATH30003- Frontiers in Human Disease > Lecture 10- Systems biology of CVD > Flashcards

Lecture 10- Systems biology of CVD Flashcards

1
Q

systems engineering approach

A

what takes inputs and transfers them to outputs?

- reverse engineer rules and predict unknown input

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

complex systems theory approach

A

need networks to understand cooperative behaviour of system

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

commonalities of systems engineering and complex systems theory approach

A
  • collection of experimental data
  • understand rules that govern behaviour of system under different conditions
  • collect data at different levels of resolution
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

reductionism

A

understand function of system by breaking it down into parts e.g. individual gene function

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

systems biology

A

understand function of system as a whole

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

normal biological systems

A

well regulated, robust to variation and damage e.g. maintain core temperature

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

disruption to normal biological systems

A

caused by mutations and environmental factors

- effects propagate across biological system

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

3 levels of resolution in biological network

A
  1. detailed- individual molecules
  2. interim- signalling pathways, metabolic networks
  3. simple interaction- one molecule interacts with another
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

3 fundamental changes in technology for systems biology

A
  1. technology- increase in measurement capabilities
  2. availability- commercialisation of techniques
  3. application- recognition of diseases at systems-level malfunction, application into biomedical research
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

human genome project and moore’s law

A

genome sequencing well beyond exponential

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

transcriptomes in medical research

A

to identify patterns of gene expression associated with a disease e.g. clinical use in cancer; Mamoprint

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

2 types of testing

A

research and clinical testing

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

research testing

A

finding unknown genes, learning how they work, developing tests for future clinical use, understand genetic conditions- results not available to patients

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

clinical testing

A

find out about inherited disorder, patients receive results, decisions about medical care e.g. reproduction

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

5 steps in systems biology approach

A
  1. define system to be examined
  2. identify components of system
  3. determine how components interact with each other
  4. model dynamics of system, mathematically, see how it changes over time, in response to disturbance
  5. validate computational model with specific experiments
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

3 systems biology in cardiovascular and heart disease

A
  1. systems biology in cardiac hypertrophy
  2. discovery of mechanisms of gene regulation
  3. population genetics and risk in CVD
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

cardiac hypertrophy

A

heart cells under stress don’t multiply, they just grow bigger- adaptive remodelling of tissue

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

what did systems biology in cardiac hypertrophy study?

A

study Ca mediated interaction between normal heartbeat system and maladaptive hypertrophic remodelling system
- insight into how cardiac hypertrophy can be turned off without adversely affecting cardiac function

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

key reason adult rat ventricular cardiomyocyte used

A

no cell cycle- dont divide, just grow bigger

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

excitation contraction coupling

A

beating of heart

  • converts electrical signal to mechanical contraction using Ca as messenger
  • expansion and contraction of Z discs
  • process regulated by regular ca influx into cell
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

features of adult rat ventricular cardiomyocyte

A

cylindrical cells, large volume, repeating structural units (Z discs), 2 active nuclei, thin cytoplasm, 30% mitochondrial volume, no cell cycle

22
Q

Ca handling proteins

A

RyRs, IP3Rs- tune properties of Ca transient/burst

-coregulate shape of overall Ca transient in cytosol and nucleus

23
Q

stimulus- transcription coupling

Ca dependent alpha adrenergic pathway

A

various protein factors interact with calcium–>gives change in transcription factor NFAT
i.e. calcium activates the Ca-NFAT system

24
Q

Ca-NFAT system

A

Calcium activates NFAT–>goes into nucleus–>causes change in transcriptional behaviour of cell
- relies on long term Ca signalling to activate transcirption associated with cardiac hypertrophy

25
Q

2 signals that coexist in same cell

A

electrical signal- regular heart beat- regular influx of calcium

growth signal- longer sustained continued presence of calcium required (to maintain NFAT in nucleus)

26
Q

3 hypotheses for how the 2 signals coexist in same cell

A

1- signals stack on top of each other
2- sustained calcium burst leads to prolonged NFAT signalling
3- restriction of calcium to certain parts of the cell

27
Q

signals stack on top of each other

A

heart beat distinguishable from growth signal

- elevated baseline, oscillation- independent, mass transit of NFAT

28
Q

sustained calcium burst leads to prolonged NFAT signalling

A

chronic micro-bursts, oscillation dependent, CaN signal integrator, NFAT accumulation

29
Q

restriction of calcium to certain parts of the cell

A

specific spatial distributions of key proteins drive Ca events locally

30
Q

line scan experiments negative and positive control

A

negative control- regular beating- consistent Ca transient

positive control- liberation of Ca within specific places temporarily raises local Ca but system quickly clears excess and returns to baseline Ca

31
Q

summary of line scan experiments

A
  • upstroke kinetics and basal Ca for both cytosol and nucleus were as expected
  • decay kinetics (sharp decline before recovery), Ca exposure, peak amplitude- different to negative controls
32
Q

what changed in line scan experiment?

A

decay kinetics, Ca exposure, peak amplitude

33
Q

what didn’t change in line scan experiment?

A

upstroke kinetics and basal Ca

34
Q

proposed mechanism of Ca control

A
  • function of IP3R mediated Ca release in heart cells NOT to potentiate RyR opening but to DELAY closing through positive feedback loops
  • ca-mediated transcriptional regulation occur during prolonged part of transient
35
Q

excess IP3 generation

A

interferes with normal intracellular recovery- causes prolonged Ca exposure

36
Q

why were hypothesis 1 and 3 not right?

A

1- no sustained uptake in baseline

3- no evidence for spatial segregation

37
Q

why was hypothesis 2 right?

A
  • decay kinetics were altered
  • NFAT TF was slowly pulsing in nucleus rather than sustained expression
  • separating hypertrophic signal form normal heart beat signal
38
Q

how are transcription factors directed and signed?

A

directed- can only go from TF to gene not other way around

signed- activator or repressor

39
Q

how do TFs and DNA interact

A

TF has a different motif/site in the DNA that it recognises

40
Q

how do proteins function?

A

dont function alone, cascades of interactions–>transduce signal
- interactome is very big

41
Q

NKX2-5 transcription factor

A

member of NK-2 Homeo-Domain (HD) class of TFs

42
Q

NK-2 Homeo-Domain (HD)

A

highly conserved, binds directly to DNA

- also serves as interaction interface with other proteins

43
Q

what does NKX2-5 recognise?

A

AAGTG

44
Q

what is NKX2-5 important for?

A

critical for heart development in fish, mouse human
- loss of NKX2-5 in mouse–>arrested heart development, blocked progenitor growth, defective chamber, embryonic lethal (10days)

45
Q

NKX2-5 mutations

A

common observed gene in congenital heart defects

- want to see whether it has role in other heart diseases

46
Q

4 consequences of NKX2-5 mutations in DNA binding domain

A
  1. altered strength of binding of TF to DNA
  2. loss of regulation- binding sites in DNA no longer recognised by TF
  3. recognition of new binding sites by TF
  4. mutations affect partner proteins that the TF can interact with (since HD interface for protein-protein interactions)
47
Q

NKX2-5 findings

A
  • change in what was regulated between WT and mutant (what genes switched on/off by mutant)
  • what proteins bound to TF and were disrupted
  • identify different binding sites indicate new interaction partners for NKX2-5
  • motifs point to specific binding partners
    SUMMARY- identify sets of genes that were differentially regulated by mutant NKX2-5
48
Q

what did population genetics and risk in CVD entail?

A

look at entire population, see which part of population is at more risk for CVD

49
Q

CVD risk factors

A

substantial minority don’t have the traditional risk factors

50
Q

genomic risk prediction

A

add genomic risk to standard risk criteria?

- less technical variation, constant over patient life, just blood sample

PATH30003- Frontiers in Human Disease (20 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions