BIOE 201Final Project Introduction
Tuesday, Sept. 23, 2014
Angiogenesis (neovascularization) growth of new blood vessels from pre-existing microvasculature
• Physiologic angiogenesis– development– exercise– wound healing– female reproductive organs
• Over 70 angiogenesis-dependent diseases – Cardiovascular disease– Breast Cancer
Non healing ulcer & gangrene- from H.Gornick, Cleveland Clinic
Bevacizumab (Avastin; Genentech): VEGF antibody
Ziv-aflibercept (VEGF Trap/Zaltrap; Regeneron): VEGF antibody
Sunitinib (Sutent; Pfizer): Tyrosine kinase inhibitor (TKI)
Sorafenib (Nexavar; Bayer & Onyx Pharmaceuticals): TKI
Anti-angiogenic therapies
• Avastin is approved for the treatment of: o Glioblastoma multiforme: most
prevalent form of brain cancero Metastatic colorectal cancer (colon
cancer)o Non-small cell lung cancero Metastatic kidney cancer
• Several side effects:o Gastrointestinal perforationo Impaired wound healingo Bleedingo HTN
Some patients are intrinsically resistant to anti-angiogenic drugsAZD2171/Cediranib/Recentin Phase II clinical trial detects decreased tumor
enhancement in over 50% of patients
Best responding patient:• Decreased tumor size• Decreased vessel size• Decreased permeability
Poorly responding patient • No change in tumor size• No change vessel size• No change in permeability
Batchelor et al (2007) Cancer Cell
The complexity of VEGF-VEGFR interactions lends itself to systems biology approaches
1 1 2 2 3 3
VEGF-A
s1
VEGF-BPlGF
VEGF-CVEGF-D
VEGF-APlGF
VEGF-D
VEGF-A121
VEGF-A145
VEGF-A165
VEGF-A189
VEGF-A209
VEGF-B167
VEGF-B186
PlGF1
PlGF2
GAG
VEGF-A121
PlGF2
VEGF-B186
N1
N2
VEGF-A145
VEGF-A165
VEGF-CPlGF2
VEGF-A165
VEGF-B167
VEGF-B186
PlGF2
1 2 32
s2
s3
VEGF-A121
VEGF-A145
VEGF-A189
Exons 1-5VEGF-A206
VEGF-A165a
VEGF-A165b
876a 6b
Exons 1-5 876a
Exons 1-5 97
Exons 1-5 87
Exons 1-5 86a
Exons 1-5 8
VEGF-A183Exons 1-5 876a*
ECM bound
PlGF1
PlGF2 Exons 1-5
Exons 1-5
6 7
7
VEGF-B167 Exons 1-5 6a7
VEGF-B186 Exons 1-5 6a6b
VEGF-CVEGF-B
Systems biology can be used to examine signaling through receptors
Final project
• Develop a systems biology approach for determining how to best target the VEGF-VEGFR signaling axis in angiogenesis.
• Using the tools learned in Module 1: Mass Balances:– Systemically examine how signals enter cells (ligand-
receptor binding)– How they generate cellular response (second-
messenger signaling)– How these signals can be best targeted by drugs
(mAbs, small molecules, etc.).
Goals1. Determine angiogenic disease you want to treat.
2. Create a mathematical model simulating VEGF-VEGFR ligand-receptor reaction network in this disease.
3. Determine which molecule or molecules you will target within the VEGF-VEGFR reaction network.
4. Quantitatively evaluate the effectiveness of your strategy via model.
5. Demonstrate the value of your quantitative analytical framework by using it to compare your strategy to current drugs.
Deliverables
• Mid-Semester Project: (presentation and 5 page progress report)– Tuesday, October 14, 2014 (Teams 1-3)– Wednesday, October 15, 2014 (Teams 4-10)
• Final Project: (presentation & report):– Tuesday, December 2, 2014 (Teams 8-10)– Wednesday, December 3, 2014 (Teams 1-7)
Mid-Semester Project Report
• Importance of VEGF pathway in disease• Ligand-receptor dynamics• Second messenger signaling pathways• Prior modeling• Approach • Preliminary results• Next steps
Mid-Semester Project Report
• Importance of VEGF pathway in disease: Your group’s disease of interest. What therapies are currently available to treat this disease?
• Ligand-receptor dynamics: What are the VEGF ligands? What are the VEGFRs? Where are these receptors located? What are the kinetics of binding (on/off rates)?
• Second messenger signaling pathways: Which downstream molecules are activated by the VEGF-VEGFR axis?
Mid-Semester Project Report• Prior modeling: Do other models exist that
focus on this pathway? If so, which ones, and what did they identify?
• Approach: What will you model? How will you do it?
• Preliminary results: any simulation results• Next steps: what you need to bring it all
together
Final Report Structure• Your report should include sufficient section
headings to guide the reader through your main points.
• You must include the following: – Title Page– Table of Contents– List of Figures/Tables– Introduction– Mathematical Framework– Simulations– Results and discussion– Bibliography– Appendices– Figure and Table Legends
Title Page
• Title of your project• Your team number• Names of team
members • Abstract: one
paragraph summary with a description of major findings.
Inhibition of the CD95 Cell Proliferation Pathway to Treat Cancer
Team #3 John Doe, Jane Asdf, Ali Ansari
Project Summary Mathematical modeling of interactions in the CD95 pathway can show both an apoptotic pathway and a cell proliferation pathway. The death receptor, CD95, and ligand, CD95L, are both found in high concentrations in biological systems afflicted with cancer. Through mathematical modeling in Simbiology, a monoclonal antibody (mAb) is introduced to the system to first inhibit the ligand and then receptor independently in order to decrease progression down the cell growth pathway. Inhibiting the ligand or receptor have similar effects in inhibiting the production of NF-κB, thus decreasing the rates of cell proliferation. In order to increase the activity of the apoptotic pathway, it is more effective to introduce the mAb downstream in the CD95 pathway to block NF-κB production and increase levels of caspase.
Table of Contents• The table of contents
should be included at the beginning of your report
• Includes: – accurate listing of
headings– sub-headings, – appendices
• All pages should be numbered
List of Figures/Tables• After the Table of
Contents, include:– List of Figures– List of Tables
• List of Figures: each of the figures found in the report with page numbers.
• List of Tables: each of the tables found in the report with table numbers.
Body of Report
• Introduction: motivation, an analysis of previous approaches, and the background necessary to understand the question you were asked to solve.
• Mathematical Framework: includes the equations that you used with a full description of these equations and a figure that represents your system.
• Simulations: what simulations did you carry out and why?
• Results and discussion: present a concise summary of your results (using figures and/or tables)
Bibliography• Any information, ideas, figures, content, etc. obtained
from another source must be cited.• Reference Managers:
– Refworks (free)– Mendeley (free)– Endnote (paid)
• Citations should follow American Psychological Association, 6th Edition (APA 6th) format.
Appendices• All feedback (student, TA, and professor)
must be included as an appendix. • Including:
– any reports/slides with comments– ALL evaluations
• You must compile feedback and include a point by point discussion of how you addressed instructor, TA, and student critique in your report.
Figure and Table Legends
• A legend should include a title and a description of the key elements in the figure/table.
• Each figure should include a figure legend below the figure
• Each table should include a table legend above the table.
Formatting• The text should not exceed 5 pages.
– Limit your figures to 1 model figure,– 1 parameter summary table, – Up to 4 simulation results/data figures.
• The following sections are not included in the page limit: – Title Page– Table of Contents, – List of Figures/Tables, – Bibliography, – Appendices
• Single spaced• ½ inch margins• Arial Font, Font size 11• All pages should be numbered
Rules for good ppt presentations
Use University of Illinois templates:• http://identitystandards.illinois.edu/
graphicstandardsmanual/othermedia/powerpoint.html
• Many template options…
Rules for good ppt presentations• Font sizes should be 18+
• Font type should be a sans-serif (e.g., Arial, Calibri) • Font color should follow the theme• Check speling and grammar¡• Headings should be descriptive• Animations should be tasteful• Bullet points imply a list and should not be alone…
they’re when not in community w/ other bullet points
• Color pictures should have a dark background• Cite EVERYTHING
Background color is important for color figures
Imoukhuede et al. (2009) Biophysical J
Background color is important for color figures
Imoukhuede et al. (2009) Biophysical J
Cite within the slide! Do not save citations until the end!
Imoukhuede et al. (2009) Biophysical J
Graphs have a professional appearance
Good Graph What to check…• Label axes• Font type and size 18+• Use scales that make
sense (usually start @ 0)• Data points/Line graph
(colors/style)• Simple colors• Enclose data with axes• Origin preferred graphical
software (free @ webstore)
How to prep a bad graph
Bad Graph Reasons• No label on axes• Missing axes• Unprofessional font• Unreadable font size• X-axis has too many
increments• Scale does not represent data
well• Unprofessional data points/Line
graph (colors/style)
Next Steps
• Teach you modeling!• Bring your laptop to class tomorrow and
Friday• Download Matlab onto your laptop
(along with Simbiology toolbox): webstore.illinois.edu