Since the 19th century, human diseases have largely been defined by the organ system in which they are most obviously manifest, and often so at end-stage. The biomedical community now recognizes that many different diseases have common mechanisms and common intermediate pathophenotypes (e.g., inflammation, thrombosis, apoptosis, and fibrosis). Based on this perspective of disease pathogenesis, the site of disease expression may be viewed a consequence of the local environment and of the differential expression of determinants of the intermediate pathophenotype in that environment. We, therefore, propose as a central hypothesis that different complex diseases are governed by common network- associated determinants of common intermediate pathophenotypes, and that what differentiates these complex diseases from one another is the balance among the intermediate pathophenotypes, and the molecular context within which they are expressed. To test this hypothesis, we will focus on three different diseases-acute myocardial infarction, venous thromboembolism, and acute ischemic stroke-and two intermediate pathophenotypes-inflammation and thrombosis-via three interdisciplinary specific aims. First, we will develop network models of pathways that govern inflammation and thrombosis. Concomitantly, we will utilize two large population-based whole genome scans to perform structured genetic analysis to identify components of inflammatory and thrombotic pathways related to the different diseases. By combining this genetic analysis with network models, we will begin to construct subnetwork maps of elements of the 'inflammasome'and 'thrombosome'common to these diseases and elements that distinguish them from one another. Second, using data sets derived from trials of the anti-inflammatory agent, rosuvastatin, and the antithrombotic agent, aspirin, in initially healthy individuals, we will examine the effect of therapeutic perturbation of the inflammasome and thrombosome on the incidence of each disease as determined by gene status. We will also utilize key molecular mediators of the inflammasome and thrombosome common to and distinctive for these three diseases in correlative, iterative mechanism studies using relevant cell systems and animal models. Third, we will integrate the network models of inflammation and thrombosis to develop predictive, probabilistic, multivariate models of manifestations of these diseases.

Public Health Relevance

Taken together, these complementary interdisciplinary approaches focused on three common chronic illnesses should provide information about and potential strategies for redefining these diseases in a mechanistically and molecularly rigorous way. If this approach is successful, it will afford the biomedical community the opportunity to redefine many complex human diseases, leading to potentially novel therapeutic and preventive strategies, and promoting the development of truly personalized (individualized) medicine.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL108630-02
Application #
8322781
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M2))
Program Officer
Qasba, Pankaj
Project Start
2011-08-18
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$687,514
Indirect Cost
$321,274
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Kitsak, Maksim; Sharma, Amitabh; Menche, Jörg et al. (2016) Tissue Specificity of Human Disease Module. Sci Rep 6:35241
Ridker, Paul M; Rifai, Nader; Bradwin, Gary et al. (2016) Plasma proprotein convertase subtilisin/kexin type 9 levels and the risk of first cardiovascular events. Eur Heart J 37:554-60
Guney, Emre; Menche, Jörg; Vidal, Marc et al. (2016) Network-based in silico drug efficacy screening. Nat Commun 7:10331
Ghiassian, Susan Dina; Menche, Jörg; Chasman, Daniel I et al. (2016) Endophenotype Network Models: Common Core of Complex Diseases. Sci Rep 6:27414
Bertero, Thomas; Oldham, William M; Cottrill, Katherine A et al. (2016) Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. J Clin Invest 126:3313-35
Zaman, Paula; Wang, Julia; Blau, Adam et al. (2016) Incorporation of heparin-binding proteins into preformed dextran sulfate-chitosan nanoparticles. Int J Nanomedicine 11:6149-6159
Garmaroudi, Farshid S; Handy, Diane E; Liu, Yang-Yu et al. (2016) Systems Pharmacology and Rational Polypharmacy: Nitric Oxide-Cyclic GMP Signaling Pathway as an Illustrative Example and Derivation of the General Case. PLoS Comput Biol 12:e1004822
Barroso, Madalena; Kao, Derrick; Blom, Henk J et al. (2016) S-adenosylhomocysteine induces inflammation through NFkB: A possible role for EZH2 in endothelial cell activation. Biochim Biophys Acta 1862:82-92
Aghamohammadzadeh, Reza; Zhang, Ying-Yi; Stephens, Thomas E et al. (2016) Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension. FASEB J 30:2511-27
Wang, Rui-Sheng; Loscalzo, Joseph (2016) Illuminating drug action by network integration of disease genes: a case study of myocardial infarction. Mol Biosyst 12:1653-66

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