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