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BMS661: PROTEOMICS > C7 > Flashcards

C7 Flashcards

1
Q

Explain protein & diseases

A
  • Arise due abnormal protein
  • Can be diagnose or treated at DNA, RNA or proteins levels
  • At each stage, disease related protein can potentially act as biomarker & therapeutic target
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2
Q

Various role of protein & their potential for manipulation such as

A
  • Initiation of diseases
  • Development of diseases
  • Outcome of disease
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3
Q

Explain cystic fibrosis

A
  • caused by changes in ion channel
  • Unable to regulate Cl ion movement
  • Cause thick, sticky mucous that affect lungs
  • cause bone problem & mobility
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4
Q

Symptoms of cystic fibrosis

A
  • Bad cough
  • Repeat chest infection
  • Diarrhoea
  • Poor weight gain
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5
Q

Explain cystic fibrosis gene

A
  • 3 bp deletion that lead to Del580
  • 27 exon
  • CFTR: 1440 amino acid
  • 2 ATP binding cassettes
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6
Q

Effects of Cl- ion movement

A
  • Na constantly pump out of cell
  • Flow of Cl out of cell provide counter ion effect
  • Allow graduent of NaCl to build up
  • Water move from blood vessel to epithelial in response to NaCl gradient
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7
Q

What happen to ion movement if CFTR gene defective

A
  • Water movement inhibited
  • Produce thick mucus
  • Effect lungs
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8
Q

Example of drug for cystic fibrosis

A
  • Genistein
  • Phenylbutyrate
  • Osmolites
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9
Q

Explain protein misfolding disease

A
  • Not involve changes in genome
  • Group of diseases share the same pathophysiology
  • Arise from normal protein in body that undergo changes in shapes
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10
Q

Example of protein misfolding disease

A
  • Transmissible spongiform encephalopathies (TSE)
  • Alzheimer
  • Parkinson
  • Type 2 diabetes
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11
Q

Pathophysiology of protein misfolding disease

A
  • Abnormal protein
  • Aggregates
  • Froms amyloids
  • Plague
  • Holes
  • Sponge
  • Death
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12
Q

Explain TSE

A
  • Involve formation of plaque & holes in brain
  • Loss of control, dementia & death
  • Cause by prions (proteninaceous infectious agent)
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13
Q

Types of TSE

A
  • Scarpie: sheep
  • BSE & Mad cow: cow
  • Kuru & CJD: Human
  • CJD, GSS & Fatal Familial insomnia: Familial
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14
Q

Explain prion

A
  • Named as PrP (prion protein)
  • Size in 27-30 kDa
  • Found in normal cells
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15
Q

Difference between PrPc & PrPSc

A

PrPc
- Normal prion
- On surface of neurons
- Bind to Cu ions
- Digested by proteinase K

PrPSc
- Abnormal prion
- Aggregate to form structure amyloid fibres
- Accumulate to from plaque
- Protease resistant

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16
Q

How PrPSc convert all PrPc to abnormal

A
  • Infection with PrPSc convert normal PrP from contaminated brain products or surgery tools
  • PrPSc resistant to autoclave
  • Denature PrPSc can renature
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17
Q

Explain Alzheimer disease

A
  • Cause by abnormalities of amyloid beta & Tau protein
  • Coded by APP gene
  • Crucial for neuron growth, survival & repair
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18
Q

Mechanism of Alzheimer disease

A
  • APP cut into smaller amyloid beta peptide which form amyloid plaques
  • Tau become hyperphosphorylated which aggregate to lead to brain shrinkage
19
Q

Explain parkinson disease

A
  • Protein a-synuclein - unknwon function
  • Exist as membrane bound a helices in cytoplasm
  • Change shape to b sheet like oligomer & aggregate into fibrils and to Lewis bodies
20
Q

Explain type 2 diabetes

A
  • Amylin - islet amyloid polypeptide
  • Produce by beta cell in pancreas
  • Hormone that acts in glycemic control (role of insulin)
  • Aggregate into fibrils & kill beta cell
  • Cause diabetes
21
Q

Possible therapy for protein misfolding disease

A
  • Re-chaperoning
  • Use small molecule to stabilise protein in correct form
22
Q

Diseases development occur due to

A
  • Accumulation of abnormal protein
  • Action of subsequent abnormal protein
23
Q

Action of subsequent abnormal protein include

A
  • Cell escape from original sites
  • Protection against immune system
  • Mediating metastasis
24
Q

Example of abnormal expression

A

MUC1 in breast cancer
- Glycoprotein of MUC1 abnormally expresedd
- Normally, cell adhere to each other & line on basal membrane
- Charged glycan on MUC1 form protective shield for the cell
- Abnormal will prevent cell adherence, charge glycan MUC1 repel each other & escape to metastasis

Her-2/neu In breast cancer
- Is a growth factor receptor that bind to growth factor to start cell proliferation
- Breast cancer cell over expressed to bind with excess growth factor
- Cause hyper proliferation & metastasis

25
Q

Function of abnormal protein as therapeutic target

A

Aim to destroy function of disease related protein & improve or cure diseases

26
Q

Explain protein for screening & diagnosis

A
  • Majority of disease marker is protein
  • Protein marker more reliable the closer they are to site of disease
27
Q

Why tissue sample or other sample not use as biomarker

A
  • Too complex for analyis
  • Screening require biopsy
  • Some are difficult to obtain in sufficient amounts
28
Q

Example of protein biomarker

A
  • Prostate specific antigen (PSA)
  • MUC1 glycoprotein
  • Her-2/neu protein
29
Q

What is the most accurate marker to date

A

Prostate specific antigen (PSA)

30
Q

Biomarkers measure from patient to indicate

A
  • Stage of disease
  • Disease or healthy
  • Response to treatment
  • Best therapy option
31
Q

Define biomarker

A

A characteristic that objectively measure & evaluated as indicator of normal biological process, pathogenic or pharmacological response to therapeutic intervention

32
Q

Explain biomarker

A
  • Indicator of particular disease of a patient
  • Individual marker, lanel of marker, signature
33
Q

Pros of biomarker

A
  • Minimally invasive
  • Cheap & quick
  • Secreted by disease tissue only
  • Highly sensitive
  • Highly specific
34
Q

Define specificity of biomarker

A
  • Percentage of people who test negative for specific disease among group of people dont have the disease
  • No test is 100% specific because some people dont have the disease will test positive (false positive)
35
Q

Explain sensitivity in biomarker

A
  • Percentage of people who test positive for specific disease among group who have the disease
  • No test has 100% sensitivity because some people who have the disease test negative (false negative)
36
Q

5 types of biomarker

A
  • Translation
  • Disease
  • Toxicity
  • Efficacy
  • Target
37
Q

Explain protein as biomarker

A
  • Better markers than genes
  • Most cancer marker are protein
  • Drug target protein
  • Common across diseases
38
Q

Explain proteomics to mine biomarker

A
  • Find a disease by looking for changes in protein profile of tissue
  • Promising for early diagnosis & monitoring prognosis of cancer
  • Use 2D gel & MS
39
Q

Example of tumor associated biomarker

A
  • PSA
  • Monoclonal protein
  • AFP
  • Beta HCG
40
Q

Steps to find biomarker

A
  • Discovery: select sample for comparison
  • Identify candidates biomarker using 2D or MS
  • Select panel of potential biomarker
  • Qualification of biomarker panel
  • Verification & validation
  • Develop clinical test based on validated biomarker
41
Q

Steps for biomarker validation

A
  • Retrospective study: compare diseases & non disease
  • Prospective study: ability to detect disease before become clinically apparent
  • Prospective sceering study
  • Randomise clinical trial
42
Q

Challenges in biomarker discovery

A
  • Sensitive enough to avoid false negative
  • Safe for consumption
  • Reproducible
43
Q

Why validation of biomarker difficult

A
  • Disease phenotype vary
  • Large sample size
  • Phenotype affected by age, sex
  • Lack of standards
44
Q

Form of validation

A
  • Biomarker validation
  • Assay validation

BMS661: PROTEOMICS (6 decks)

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