Elsevier in the Classroom

Using Pathway Studio as a tool in the college classroom to teach science interactively

Elsevier in the Classroom Using Pathway Studio as a tool in the college

classroom to teach science interactively

Program Components

• Pathway Studio licenses will be provided to teachers and students for the duration of the teaching period free of charge

• Teachers will be provided with a series of Pathway Studio teaching module examples designed to provide comprehensive training in the full use of the Pathway Studio software set within a Systems Biology context.

• Additional instructional assistance will be available in the form of pre-recorded webinars

• Structured feedback will be requested from teachers during and at the end of each course in order to provide data for future program modifications

• Collaborations will be offered as requested for the development of targeted course curriculum

• Participation in the publication of teaching results in education journals will be encouraged

• Pilot programs have already been initiated at Georgetown University, and will be extended to Virginia Commonwealth University (VCU), MD Anderson, and Northeastern.

• Going forward, we will target universities on the strategic top 100 list, and also those that are clustered near major pharmaceutical hubs (e.g. Boston).

• Teaching of courses to begin as soon as the Fall Semester, 2016

Sample Teaching Module

Elsevier in the Classroom

Pre-eclampsia or preeclampsia (PE) is a disorder of pregnancy characterized by high blood pressure and a large amount of protein in the urine. The disorder usually occurs in the third trimester of pregnancy and gets worse over time. In severe disease there may be red blood cell breakdown, a low blood platelet count, impaired liver function, kidney dysfunction, swelling, shortness of breath due to fluid in the lungs, or visual disturbances. Preeclampsia increases the risk of poor outcomes for both the mother and the baby. If left untreated, it may result in seizures at which point it is known as eclampsia.

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Elsevier in the Classroom; Training Module 1 (disease-centric analysis)

1

Find all pre-eclampsia disease relations with protein as an entity type, select all reference >=10

What are the most important proteins related to pre-eclampsia as found in the scientific literature?

SAVE ALL WORK!

2

Select protein most highly cited in connection with pre-eclampsia (FLT1) Find proteins (transcription factors) that bind to the promoter of FLT1 Highlight most cited transcription factor for FLT1 (HIF1A)

What is the single most highly cited protein related to pre-eclampsia and what is it’s most common transcription factor?

SAVE ALL WORK!

3

Find predicted miRNAs that may regulate expression of FLT1

SAVE ALL WORK!

Highlight predicted (red) vs experimental (green) miRNAs for FLT1

Are there any miRNAs which affect the expression of the FLT1 gene? 4

Find proteins, protein complexes, protein functional classes, and small molecules that are involved in the expression FLT1, either directly or indirectly (references >=10)

SAVE ALL WORK!

Highlight protein functional classes (red) and protein complexes (green)

5

Identify groups of genes (from the list of proteins most strongly associated with pre-eclampsia - slide 2) that share common expression regulators using Sub-Network Enrichment Analysis (SNEA).

Under Custom select type, use “upstream” as the direction, “Protein” as the entity (seed), and “PromoterBinding” as the relation.

Name Total # of Neighbors Gene Set Seed Overlap Percent Overlap Overlapping Entitiesp-value Jaccard similarityHit type

Downstream Neighbors of JUN 331 JUN 24 7 EDN1;INHBA;MIR155;ACE;VEGFA;IL6R ligand;HSPA1A;TNF;FN1;TGFB1;adiponectin;IL8;IL10R ligand;HLA-G;VCAM1;GSTP1;HIF1A;SELE;gelatinase B;NOS3;SERPINE1;ICAM1;CRH;FLT11.79E-19 0.069565 Downstream Neighbors

Downstream Neighbors of HIF1A 248 HIF1A 17 6 EDN1;ADM;HIF1A;ACE;VEGFA;IL6R ligand;gelatinase B;HSPA1A;TNF;AGT;SERPINE1;LEP;TGFB1;r_Eng;adiponectin;FLT1;IL87.76E-13 0.063197 Downstream Neighbors

Downstream Neighbors of ATF2 89 ATF2 12 13 ACE;HIF1A;VEGFA;SELE;NOS3;gelatinase B;TNF;SERPINE1;FN1;ICAM1;FLT1;IL81.5E-12 0.104348 Downstream Neighbors

Downstream Neighbors of EP300 220 EP300 16 7 EDN1;VCAM1;HIF1A;VEGFA;NOS3;IL6R ligand;gelatinase B;HSPA1A;TNF;AGT;SERPINE1;LEP;FN1;ICAM1;TGFB1;IL81.89E-12 0.066116 Downstream Neighbors

Downstream Neighbors of CEBPB 300 CEBPB 16 5 CRP;EDN1;ADM;GSTP1;VEGFA;IL6R ligand;TNF;AGT;LEP;ICAM1;CRH;INHA;TGFB1;adiponectin;IL8;IL10R ligand2.16E-10 0.049689 Downstream Neighbors

Downstream Neighbors of ETS1 170 ETS1 13 7 VCAM1;ACE;VEGFA;NOS3;gelatinase B;TNF;SERPINE1;FN1;ICAM1;TGFB1;FLT1;IL8;IL10R ligand2.16E-10 0.066667 Downstream Neighbors

Downstream Neighbors of FOS 171 FOS 13 7 VCAM1;MIR155;GSTP1;VEGFA;IL6R ligand;gelatinase B;TNF;SERPINE1;FN1;ICAM1;TGFB1;adiponectin;IL82.33E-10 0.066327 Downstream Neighbors

Downstream Neighbors of STAT3 309 STAT3 16 5 CRP;ADM;MIR155;HIF1A;VEGFA;IL6R ligand;NOS3;gelatinase B;HSPA1A;AGT;SERPINE1;ICAM1;TGFB1;adiponectin;IL8;IL10R ligand3.36E-10 0.048338 Downstream Neighbors

Downstream Neighbors of EGR1 232 EGR1 14 6 ACE;HIF1A;VEGFA;IL6R ligand;gelatinase B;TNF;SERPINE1;FN1;ICAM1;PGF;TGFB1;AGTR1;FLT1;IL88.51E-10 0.054688 Downstream Neighbors

6

SAVE ALL WORK!

Highlight the pre-eclampsia genes for the two most common upstream expression regulators (JUN in red, HIF1A in green) as revealed in the SNEA analysis (SEE BELOW FOR HELP).

How many of the pre-eclampsia genes (from slide 2) share either of the top 2 FLT1 transcription factor regulators?

Pathway Studio Trick # 1!

7

This may not be obvious (at first!), but the way to highlight proteins/genes in a pathway view with information from another group is actually quite easy! Just follow the trail of bread crumbs below.

So, in the current example, in slide 7, we generated a list of the most common upstream regulators for the pre-ecalampsia related genes (from slide 2) using the SNEA tool. The top 2 entries (sorted by p-value) in that list (as found in the table below the pathway viewer) are JUN and HIF1A.

8

To view the overlapping genes (from your target list) with the list of all the potential targets of say, in this case, the JUN transcription factor, just double-click on the particular list entry in the table, and….voila, now those genes (and those genes only) are displayed in the pathway viewer.

1 Downstream Neighbors of JUN

9

Now, here’s the big trick-> if you want

to highlight just those genes in another pathway, all you have to do is: select and copy them, now go to the other pathway (drum roll, please!) and … Select clipboard content and then Highlight with the color of your choice (hint: if you are going to highlight more that once , the second time use a Mix-in contrasting color so you can see both highlights together).

2

See how easy that was? Now, why don’t you try it with HIF1A!

10

HIF1A is not only one of the most important regulators of the FLT1 gene (which in turn is the single most highly cited gene in reference to pre-eclampsia in the literature), it also appears to be a major regulator for a significant number (17/41) of all the pre-eclampsia associated genes. This is beginning to look interesting, so what can we tell about the biological processes controlled by HIF1A?

Well, first of all, we could Identify all the genes with promoters known to be bound by HIF1A.

Hint: Copy and paste HIF1A into new pathway, select HIF1A, select add neighbors, (downstream), select Protein as the entity type and PromoterBinding as the relation type

11

SAVE ALL WORK!

Now we can ask ourselves; of all the genes under the potential control of HIF1A, what are some of the most common biological processes involved?

Select all from slide 11, go to tools, select enrichment analysis, analysis type = find pathways, choose from the GO sets; biological processes, and then select ‘find’.

12

The most enriched GO biological process for the HIF1A transcriptome is…? What diagnostic parameter (see slide 1) of pre-ecalampsia does this finding make the most sense of? Discuss with class.

13

14

Are you ready for a little bit more?

What about the drugs and possible drug treatments that are used for handling patients (i.e. pregnant women) at risk for preeclampsia?

We have two quick ways (at least!) of investigating that question using Pathway Studio

1. Test all small molecules associated in the literature with pre-eclampsia

2. Look for any clinical trials reported for pre-eclampsia treatments

15

Create a new pathway using the pre-eclampsia disease entity as a starting point. Add small molecules as an entity type and relation = regulation, effect = negative.

This will still give you a lot of relations!

So let’s filter that down a little bit by going to the Interactive Network Builder and selecting for relations with 5 or more supporting articles.

Now that’s a little more manageable! Let’s go look at the graph view.

16

Looking good!

And if we look a the relation table view and sort by the highest number of references and we find…aspirin! Try googling aspirin and pre-eclampsia and tell the class what you find.

How is MgSo4 used in the treatment of pre-eclampsia?

For what disease condition was the drug pravastatin originally developed for?

17

And finally, clinical trials

Small molecules, same as before, for relations pick ClinicalTrial

1. What are the most studied drugs in terms of number of clinical trials?

2. What is the rationale for the use of pravastatin in treating pre-eclampsia (requires linking out to the clinical trials record for answer. Hint: check Detailed Description field)

18

Overlap of Clinical Trials and Small Molecules 19