Advanced Computational Network Modeling Offers Clues To Pulmonary Hypertension Origins

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shutterstock_151194653Researchers in a major study based at Brigham and Women’s Hospital (BWH) in Boston, Massachusetts, have linked development of the deadly vascular disease pulmonary hypertension (PH) to a related family of molecules, and show that the disorder’s progression involves disparate molecular pathways that span multiple cell types. MicroRNAs (miRNAs) may coordinately regulate PH progression. The origins of PH are largely undefined, and this stud is one of the first to leverage advanced computational network modeling in deciphering the molecular secrets of this complex human disease.

The study, published online June 24, 2014 in The Journal of Clinical Investigation, entitled “Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension” (J Clin Invest. dpi:10.1172/JCI74773), is coauthored by 21 scientists associated with more than a dozen hospitals and medical institutions across the United States and two in Germany. Senior corresponding author is Stephen Y. Chan, MD, PhD of the Divisions of Cardiovascular Medicine and Network Medicine at Brigham and Women’s Hospital and an Assistant Professor of Medicine at Harvard Medical School in Boston.

Despite increasing numbers of people diagnosed with the disease worldwide, pulmonary hypertension has been a historically neglected disease that occurs when there is increased pressure in the blood vessels of the lung, thereby compromising delivery of blood and oxygen to the body. Symptoms are debilitating and initially include shortness of breath and fatigue, but if left untreated, PH can lead to right ventricular failure, volume overload, and death. However, the molecular processes by which diverse upstream stimuli result in PH remain enigmatic.

Research in the Chan laboratory at BWH centers on the complex molecular mechanisms by which the pulmonary and peripheral blood vessels respond to hypoxic or ischemic injury and thus instigate adaptive or pathogenic states.

ChanSYDr. Chan and his research colleagues have focused on the study of microRNAs, which are small, non-coding nucleic acid molecules that can block production of numerous proteins in human cells with implications in health and disease, and in particular on the pulmonary arterial vasculature as a model system and its role in the development of PH. With the help of sophisticated computational analyses, the researchers developed a unique molecular model tracing the architecture interconnecting the network of genes and microRNAs associated with pulmonary hypertension.

Using a combination of network-based bioinformatics, cell-culture based assays, rodent models of pulmonary vascular disease carrying relevant genetic miRNA deletions, and unique human samples, ongoing projects in the Chan laboratory focus on prediction and confirmation of how networks of hypoxia-relevant miRNA coordinately regulate target gene expression, intermediate functions (e.g., metabolism), and consequent vascular phenotypes in vivo. In doing so, it is the scientists’ hope that they can build a better hypoxic “disease network” for providing more sophisticated predictions of complex human disease states that currently are not possible. They say results should identify important mechanistic connections between microRNA and vascular cell biology, with translational implications for significantly improving understanding of PH and other hypoxic vascular diseases as well as offering novel possibilities for diagnosis and treatment.

The Journal of Clinical Investigation study coauthors note that development of PH involves disparate molecular pathways that span multiple cell types, and that while MicroRNAs (miRNAs) may coordinately regulate PH progression, the integrative functions of miRNAs in this process have been challenging to define with conventional approaches.

In this study, analysis of the molecular network architecture specific to PH predicts that the miR-130/301 family is a master regulator of cellular proliferation in PH via regulation of subordinate miRNA pathways with unexpected connections to one another. In validation of this model, the researchers discovered that diseased pulmonary vessels and plasma from mammalian models and human PH subjects exhibited upregulation of miR-130/301 expression, and their results provide insight into the systems-level regulation of miRNA-disease gene networks in PH with broad implications for miRNA-based therapeutics in this disease. Additionally, their findings provide critical validation for the evolving application of network theory to the discovery of the miRNA-based origins of PH and other diseases.

The coauthors observe that PH has poorly defined molecular origins, and is driven by various disparate triggers (such as hypoxia and inflammation, among others). The disease is marked by a pathologic imbalance of complex molecular pathways that in turn promote a number of cellular pathophenotypes (examples: proliferation and vasoconstriction), and it affects multiple vascular cell types, including pulmonary arterial endothelial cells (PAECs) and smooth muscle cells (PASMCs). They maintain that identification of a regulatory factor or factors that coordinately integrate(s) these vast molecular programs, would not only offer fundamental insight into the molecular genesis of PH but also greatly improve strategies for therapeutic targeting of the upstream disease origins. However, the complexity of PH has made difficult the identification of such factors by standard reductionist strategies of experimentation.

“Pulmonary hypertension is an example of a cardiovascular disease so complex that traditional methods of research have failed to provide adequate treatments to prevent or halt its progression,” says Dr. Chan in a BWH release. “We have been advancing the idea that mathematical models of this disease can be generated to perform high-volume, systematic analyses that are not feasible with standard experimentation. In doing so, we can make predictions regarding critical molecular networks that underlie the molecular origins of pulmonary hypertension that have not been possible to this point.”

“Historically, most computational approaches in the study of human disease gene networks go no further than theoretical predictions,” comments lead study author Thomas Bertero, PhD, of BWH’s Division of Cardiovascular Medicine. “We wanted to be sure that our predictions were truly valid in real instances of pulmonary hypertension.”

Consequently, the researchers confirmed their mathematical predictions with experiments using a wide range of pre-clinical and human models, and in so doing identified the microRNA family, miR-130/301, as a master regulator of diverse target genes and additional microRNAs, ultimately orchestrating a global proliferative response in diseased blood vessels leading to pulmonary hypertension.

The researchers conclude that through advanced analysis and validation of disease network architecture, they have defined a higher order of miRNA network regulation in PH by the miR-130/301 family, thus addressing a notable deficiency in reductionist experimentation and carrying broad implications for miRNA-based diagnostics and therapeutics. Consequently they say future applications of miRNA network theory should rapidly define additional upstream origins of PH and perhaps other disease conditions that link complex miRNA signaling pathways to final disease manifestations.

“This is the first microRNA family found to regulate such a diverse number of pathways specific for pulmonary hypertension, and these molecules could be very effective therapeutic targets for treating this deadly disease,” Dr. Chan explains. “Since all of these findings were previously missed by conventional experiments, our efforts also provide great support for using network modeling to discover the molecular origins of other complex human diseases.”

This research was supported by the National Institutes of Health (K08HL096834, HL67841, HL61284); the McArthur-Radovsky, Lerner, Harris, and Watkins Funds; and the Pulmonary Hypertension Association.

Brigham and Women’s Hospital (BWH, “The Brigham”), a 793-bed nonprofit teaching hospital, is the largest hospital of the Longwood Medical and Academic Area in Boston, Massachusetts. It is an affiliate of Harvard Medical School and a founding member of Partners HealthCare. With more than 3.5 million annual patient visits, BWH is the largest birthing center in Massachusetts and employs nearly 15,000 people. Through investigation and discovery conducted at its Brigham Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, more than 1,000 physician-investigators and renowned biomedical scientists and faculty supported by nearly $650 million in funding. For the last 25 years, BWH has ranked second in research funding from the National Institutes of Health (NIH) among independent hospitals.

The BWH Pulmonary Vascular Disease Program is a unique multidisciplinary program that brings together experts in both Pulmonary Medicine and Cardiovascular Medicine committed to providing the most comprehensive and compassionate care to patients referred to BWH for pulmonary vascular disease, pulmonary arterial hypertension, and chronic thromboembolic pulmonary hypertension. The unit affirms dedication to developing a plan of care individualized to patients’ needs using all resources available at the Brigham and Women’s Hospital in a clinical program designed to provide evaluation, treatment and follow-up for all patients with Pulmonary Vascular Disease.

BWH is involved in many research trials that place the facility on the cutting edge of new treatments as they emerge, and places a strong emphasis on patient education, encouraging patients to learn as much as they can about their disease and their medications. In addition to providing individualized treatment and counseling, the PH program offers access to a support group for patients and their families to share personal experiences and learn from each other.

BWH is located directly adjacent to Harvard Medical School of which it is the second largest teaching affiliate, and with Massachusetts General Hospital, one of the two founding members of Partners HealthCare, the largest healthcare provider in Massachusetts. Brigham and Women’s is also a partner in the Dana-Farber/Harvard Cancer Center, and treats patients at Faulkner Hospital, a community teaching hospital located in the Jamaica Plain section of Boston, and at Brigham and Women’s/Mass General Health Care Center at Foxborough, Massachusetts. The hospital is a Level I Burn and Trauma Center. A rooftop helipad on the BWH campus accommodates helicopter patients. BWH is part of the consortium of hospitals which operates Boston MedFlight.

For more information, visit:

Brigham and Women’s Hospital
The Journal of Clinical Investigation

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Brigham and Women’s Hospital

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