BIOE 201 Final 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 cancer o Metastatic colorectal cancer (colon cancer) o Non-small cell lung cancer o Metastatic kidney cancer Several side effects: o Gastrointestinal perforation o Impaired wound healing o Bleeding o HTN

Some patients are intrinsically resistant to anti-angiogenic drugs AZD2171/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 VEGF-A s1 VEGF-B PlGF VEGF-C VEGF-D VEGF-A PlGF VEGF-D VEGF-A 121 VEGF-A 145 VEGF-A 165 VEGF-A 189 VEGF-A 209 VEGF-B 167 VEGF-B 186 PlGF 1 PlGF 2 GAG VEGF-A 121 PlGF 2 VEGF-B 186 N1N1 N2N2 VEGF-A 145 VEGF-A 165 VEGF-C PlGF 2 VEGF-A 165 VEGF-B 167 VEGF-B 186 PlGF s2 s3 VEGF-A 121 VEGF-A 145 VEGF-A 189 Exons 1-5 VEGF-A 206 VEGF-A 165a VEGF-A 165b 876a 6b Exons a Exons a Exons 1-58 VEGF-A 183 Exons a * ECM bound PlGF 1 PlGF 2 Exons VEGF-B 167 Exons 1-5 6a 7 VEGF-B 186 Exons 1-5 6a 6b VEGF-C VEGF-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.).

Goals 1.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.

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, 6 th Edition (APA 6 th ) 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: ndardsmanual/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 GraphWhat to check… Label axes Font type and size 18+ Use scales that make sense (usually 0) Data points/Line graph (colors/style) Simple colors Enclose data with axes Origin preferred graphical software webstore)

How to prep a bad graph Bad GraphReasons 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