Literature Review Modeling of Cell Signaling Modeling of Gene by iem58695

VIEWS: 7 PAGES: 22

									Engineering Molecular Cell Biology
      Lecture 21, Fall 2009

        Literature Review:


  Modeling of Cell Signaling
Modeling of Gene Expression




        BME42-620 Lecture 21, Fall 2009   1
                   Outline
• Mathematical modeling of NF-kB signaling

• Comments on " A synthetic oscillatory
  network of transcriptional regulators"

• Review of problem set 1




               BME42-620 Lecture 21, Fall 2009   2
                NF-kB Pathway (I)
• NF-kBs are transcription regulatory
  proteins.

• NF-kB are central to many stressful,
  inflammatory, and immune responses
  and to animal development.

• Misregulation of NF-kB leads to
  chronic inflammatory diseases and
  cancer.

• Most elements of NF-kB signaling
  pathway have been mapped.

                                                          Hayden & Ghosh, Cell, 132:344, 2008.

                        BME42-620 Lecture 21, Fall 2009                                          3
                    NF-kB Pathway (II)
• NF-kB signaling pathway
  can be activated by many
  receptors
    - Toll-like receptors
    - TNF receptors
    - Cytokine receptors


• Released NF-kB
  translocates into the
  nucleus and turns on the
  transcription of hundreds
  of genes related to                                         Beutler, Nature, 430:257, 2004
  stressful, inflammatory
  and immune responses.



                            BME42-620 Lecture 21, Fall 2009                                    4
                      NF-kB Signaling
• Binding of IkB to NF-kB
  keeps NF-kB inactive.

• Phosphorylation of IkB by IKK
  triggers the degradation of
  IkB.

• Three isoforms of IkB
    - IkB, IkB, IkB

• Different isoforms of IkB play
  different functional roles.

• Triggered expression of IkB
  forms a negative feedback
  loop.
                          BME42-620 Lecture 21, Fall 2009   5
   Modeling of NF-kB Signaling Using ODEs
• Some reactions are
  omitted.

• Phosphorylation,
  ubiquitination, and
  proteasomal
  degradation are lumped
  into one reaction.

• Input: a step increase in
  IKK

• Initiation strategy



                         BME42-620 Lecture 21, Fall 2009   6
  Main Results of Modeling Analysis (I)
• Initial model (Hoffmann et al; 2002) focuses on IkB

• 34 parameters; 45 equations

• Main results
      - Different IkBs induce different reactions.
             IkB provides negative feedback and induces oscillation
             IkB and IkB dampens oscillation
      - Temporal responses
             Short stimuli induce a short phase of NF-kB response
             Long stimuli induces proportionally longer responses.
      - Differential activation of genes

                       BME42-620 Lecture 21, Fall 2009                 7
   Main Results of Modeling Analysis (II)
• Go to Biomodels
  http://www.ebi.ac.uk/biomodels-main/



• Model record
  http://www.ebi.ac.uk/biomodels-main/BIOMD0000000140


• SBML: system biology markup
  language




                                  BME42-620 Lecture 21, Fall 2009   8
        Extension of the Original Model (I)

• Multiple intracellular feedback loops
   - IkB and IkB work in tandem to ensure fast
   response and oscillation suppression.


• Extracellular feedback loops
      - LPS (lipopolysaccharide) activates TLR4
      - Trif and MyD88 are activated asynchronously
      - MyD88: fast direct activation
      - Trif: slow indirect activation


• Many other possible feedback loops




                              BME42-620 Lecture 21, Fall 2009   9
       Extension of the Original Model (II)
• IKK is chosen to be the input to the
  model.

• IKK activities are regulated.

• NF-kB dynamics is sensitive to
  timing and duration of IKK activities.

• Expression of targeted genes can be
  modulated by different temporal IKK
  signals.

• Crosstalk with many other pathways
      - LT
      - TGF
                            BME42-620 Lecture 21, Fall 2009   10
                          Outlook
• Encoding and decoding of spatial temporal
  communication

• Ration drug design through computer simulation
      - Outcome prediction
      - Efficiency analysis


• Integration with other signaling pathways

• Modeling method development
      - Parameter sensitivity analysis



                       BME42-620 Lecture 21, Fall 2009   11
                        Comments
• Definition of the module is
  critical
      - Complexity reduction
      - Functional independence


• Critical importance of
  integrating computational
  analysis and experiments

• Limitation of ODE-models
                                          Hayden & Ghosh, Genes & Dev., 18:2195, 2004


• How representative is the
  NF-kB pathway?
                         BME42-620 Lecture 21, Fall 2009                                12
A Synthetic Oscillatory Network of
   Transcriptional Regulators




          BME42-620 Lecture 21, Fall 2009   13
                    Network Design (I)
• A representative work of
  synthetic biology.

• LacI - TetR - cI forms a
  negative feedback loop.

• How it works
     - Repression of the repressors




                                BME42-620 Lecture 21, Fall 2009   14
               Network Design (II)
• Activities of the network
  depend on
     - transcription rate
     - translation rate
     - protein/mRNA decay rate

• Oscillations are favored by
    - Strong promoters
    - Low transcription
      repression leakage
    - Comparable protein decay
      rates

• Use transient IPTG impulses
  for synchronization
                         BME42-620 Lecture 21, Fall 2009   15
             Network Design (III)
• Computer simulation
  without & with noise




                     BME42-620 Lecture 21, Fall 2009   16
           Implementation

• Cell lineage
  is tracked
  manually




                 BME42-620 Lecture 21, Fall 2009   17
   Expression Levels Over Different Generations

• Different expression
  activities of daughter
  cells




                       BME42-620 Lecture 21, Fall 2009   18
               Comments

• Integration of computational analysis with
  experiments




               BME42-620 Lecture 21, Fall 2009   19
Questions?




BME42-620 Lecture 21, Fall 2009   20
             Problem Set 1

• Most of you did very well.

• Convert units first. Avoid unit conversion
  within calculations.




                BME42-620 Lecture 21, Fall 2009   21
                          Question 6.1
• Einstein-Smoluchowski Relation
                                                 2
                                             2m 2       2
   vd 
          1
            a 
                 1 Fx
                               f 
                                    Fx 2m
                                                 mvx  kT
          2      2m                 vd       2      D    D
                                               
                                        kT
                                 D                   f: viscous drag coefficient
                                         f


• Stokes' relation: the viscous drag coefficient of a rod
  rotating in an unbounded fluid
                             f  8 r 3        : viscosity
                                                r: radius




                          BME42-620 Lecture 21, Fall 2009                           22

								
To top