CMREF

The Cardiovascular Medical Research and Education Fund

Grant Awards

2016 


“FOXMI: A New Therapeutic Target in Pulmonary Arterial Hypertension.”

Sebastien Bonnet

A study to evaluate the therapeutic potential of FDI-6 (a FOXM1 inhibitor) for the treatment of PAH. In AIM1, we will test the hypothesis that FOXM1 contributes to PAH-PASMC proliferation and resistance to apoptosis. Selective pharmacological and molecular loss of function approaches will be used. In AIM2, we will identify the mechanisms by which FOXM1 regulates these processes and investigate the molecular mechanisms accounting for its overexpression in PAH-PASMCs. In AIM3, we will evaluate the therapeutic potential of 2 FOXOM1 inhibitors (FDI-6 and a cell-penetrating ARF peptide inhibitor) on exercise capacity, pulmonary hemodynamic variables and right ventricular function in the Sugen/Hypoxia-induced PAH rat model. 


“Study of Microparticles of High Altitude Induced Pulmonary Hypertension in Kyrgyz Highlanders.” 

Hossein Ardeschir Ghofrani and Djuro Kosanovic
We hypothesize that various endothelial and inflammatory cell-derived MPs possess all required properties and characteristics to represent promising future biomarkers for the patients with HAPH. Furthermore, we hypothesize that prominent cold exposure, frequently present “companion” associated with hypoxic condition at high altitude settlements, may have additional detrimental effects on patients with HAPH and may further alter the MPs profile. According to our hypotheses, we will address the following questions:

1) What is the expression level of various endothelial and inflammatory cell-derived MPs in the peripheral blood of Kyrgyz highlanders with or without HAPH compared to the low-land control group? Is there any influence of the cold exposure on MP expression profiles in different patient groups?, and

2) In order to characterize whether MPs are promising biomarkers, is there a correlation between circulating MP levels and clinical parameters measured by echocardiography, such as systolic pulmonary arterial pressure (PAP), mean PAP, pulmonary artery acceleration time (PAAT), cardiac index (CI) and pulmonary vascular resistance (PVR) in different human subject groups? 


"Precision Medicine Initiative for Pulmonary Vascular Disease​"

John H. Newman, M.D. and Stuart Rich, M.D.

An ongoing multifaceted project that will create a template for a precision medicines approach that will be used for new drugs. A workshop including the NHLBI and FDA initiated the process. To follow will be the designation of a task force that will have several working groups develop guidelines for the different facets of clinical trials. Guidelines for phase II clinical trials in this field will be created and disseminated. An initial project that will seek to identify a unique phenotype of patients that may be responsive to a select tyrosine kinase inhibitor will be conducted. This will be followed by a proof-of-concept clinical study using the precision medicine approach. 


“PPHNet BIOspecimen Laboratory Depot”

Eric D. Austin
Aim 1: To establish a biospecimen respository linked to the meticulously phenotyped PPHNet patient and family cohort. The PPHNet BiOspecimen Laboratory Depot (PPHNet-BOLD) will provide a resource of DNA, RNA, plasma, serum, and circulating peripheral blood mononuclear cells for investigators studying pediatric PH. Based upon current PPHNet enrollment numbers, we anticipate over 200 subjects per year including over 50 new PH diagnoses. PPHNet-BOLD will be housed at All Children’s Hospital Johns Hopkins Medicine, and overseen by the PPHNet Steering Committee. 


Aim 2: To determine the frequency of known PH-associated gene mutations in pediatric PH. We will use next generation sequencing coupled with MLPA to comprehensively screen for mutations in the BMPR2, SMAD9, CAV1, KCNK3, ALK1, ENG, EIF2AK4 genes. This approach should detect not only point mutations and small insertions/deletions, but also exonic deletions and duplications in the genes of interest and add critical information to frame the detailed clinical outcomes already captured by the PPHNet.


Aim 3: To promote and distribute samples and genotype/sequence data maintained at the PPHNet-BOLD repository. All biological samples, clinical data, as well as the PH-specific sequencing data for these subjects will be made available to the scientific community. A small review committee comprised of investigators from PPHNet contributing centers to the repository will review proposals requesting any samples and/or genotype data. Upon approval and after successful execution of a material transfer agreement (MTA), any requested samples will be supplied to the approved investigators. 
The impact of this resource on the study of pediatric PH will be highly significant. We will create a resource of biological samples and data that will benefit every investigator interested in pursuing pediatric PH-related research. The proposed resource has generated tremendous support not only from the PPHNet enrolling centers, but from many centers which hope to join the PPHNet collaborative. 


2015


“PHA Patient Registry.” 

PHA Association
A grant to support the development and implementation of the PHA Patient Registry that will serve as a resource to help find ways to prevent and cure pulmonary hypertension.

SPECIFIC AIM #1: Measure and improve quality of care

SPECIFIC AIM #2: Understand risk factors for outcomes in PAH and CTEPH patients

SPECIFIC AIM #3: Facilitate funded clinical research studies in PAH/CTEPH

"Pulmonary Circulation Journal"

Pulmonary Vascular Research Institute

A grant in support of the launch of Pulmonary Circulation, the first peer reviewed scientific journal to publish original research articles, review articles, case report, and guidelines that are related to the pulmonary circulation, pulmonary vascular disease and lung injury.


“Adaptive and Maladaptive Coupling of the Right Ventricle and Pulmonary Circulation.” 

Grover Conference
This conference examined the interaction between the right ventricle and the pulmonary circulation as it occurs during development, in normal physiology and in disease states, notably pulmonary hypertension and congenital heart disease. The goal of this conference is to bring basic and translational scientists and physicians who deal with the pulmonary circulation and the right ventricle together to discuss the normal and disordered mechanisms by which the RV and pulmonary circulation are coupled.


“Immune and Inflammatory Cell Involvement in the Pathology Schistosomiasis induced Pulmonary Arterial Hypertension.” 

Ghazwan Butrous
A proposal to undertake a multiple approach in order to unveil actual characteristics of granulomas in the lung to systematically evaluate the number and cross-sectional distribution of inflammatory cells in different sizes of pulmonary arteries from the lungs of mice infected with schistosomiasis after 8 and 12 weeks and developed pulmonary vascular remodeling versus control uninfected healthy lungs.


“Network Medicine and Vascular Fibrosis in Pulmonary Arterial Hypertension.”

Bradley Maron
This project aims to Identify treatment targets to abrogate pulmonary vascular fibrosis.

SA1: Demonstrate that NEDD9 accumulation defines maladaptive fibrosis in PAECs in vitro.

Hypothesis: Increased reactive oxygen species generation stimulated by ALDO occurring in PAECs promotes NEDD9 cysteinyl thiol oxidation and prevents NEDD9 degradation by Smad3 to sustain TGF-ß1-mediated collagen formation, which is a defining molecular mechanism of maladaptive fibrosis.

(1) Characterize the oxidant stress and NEDD9 expression profile differences in [ALDO-treated PAECs and dermal microvascular endothelial cells (DMVECs) in vitro, which are cell types associated with pathogenic and physiologic fibrosis, respectively.

(2) Use proteomics and Raman spectroscopy to characterize NEDD9 cysteinyl thiol oxidation states in PAECs and DMVECs, and the derivative consequences on NEDD9-Smad3 binding.

(3) Demonstrate that by inhibiting TGF-ß1 signaling through NEDD9 antagonism with NEDD9-siRNA, fibrillar collagen synthesis is attenuated in ALDO-treated PAECs.

SA2: Establish that NEDD9 contributes to pulmonary vascular fibrosis and PAH in vivo.

Hypothesis: Upregulation of pulmonary endothelial NEDD9 functions as a critical molecular lynchpin regulating pulmonary vascular fibrosis in vivo, which in PAH promotes cardiopulmonary dysfunction.

(1) Treat Sugen-5416/hypoxia-PAH rats, which express hyperALDO, with aerosolized NEDD9-siRNA or vehicle to demonstrate that molecular inhibition of NEDD9 attenuates maladaptive pulmonary vascular fibrosis to maintain/restore normal right ventricular (RV)-pulmonary arterial physiology (i.e., RV-pulmonary arterial coupling) and improve exercise capacity in PAH in vivo.

(2) Demonstrate definitively NEDD9 involvement in the development of pulmonary hypertension and pulmonary vascular fibrosis by analyzing pulmonary vascular histopathological changes and cardiopulmonary hemodynamics in transgenic NEDD9-/- mice exposed to hypoxia.


“The Establishment Of The Center For Clinical Data Integration.”

Steven Kawut
This will be a data repository and sharing platform for clinical trials in pulmonary hypertension, both previous and future. The long-term goal of this initiative is to accelerate the development of more effective treatments for PH by collecting and curating data from prior (and future) clinical trials of drugs, medical devices, management strategies, and biologics performed by academic investigators and industry. The deliverables of this initiative would include the:

1) Deep phenotyping of clinical trial participants to determine a more personalized approach to treatment, which could target certain treatments to patients with a higher chance of response (or avoid such treatments in patients with a greater risk of adverse events)

2) Ability to identify important and novel factors of disease progression and survival

3) Leveraging of biomarkers collected in the setting of the parent studies to guide treatment and to validate novel end points for future clinical trials

4) Creation of a “master” data infrastructure which could expedite future clinical trials in PH and facilitate harmonization 


2014 


"The Leh Symposium"

Qadar Pasha

A symposium to discuss recent trends of integrating all branches of research on high-altitude and bring them to a common global platform for long term future perspectives.


“The Annual Drug Discovery and Development Symposiums for Pulmonary Hypertension”

Pulmonary Vascular Research Institute
The goal of these symposiums is to bring together the essential stakeholders (academia, industry, and regulatory) to present and critique the latest discoveries of treatments for pulmonary vascular diseases. 


2013


“Instantaneous And Non-Invasive Measurement Of Pulmonary Artery Pressure By Acoustic Analysis (Advanced Signal Processing) Of The Second Heart Sound.” 

Ian Adatia
This project showed that the entropy of the first sinusoid formant at the 2nd LICS was significantly lower in subjects with PAH, yielding a classification into PAH and normal with a sensitivity of 93% and specificity of 92%. The reduced entropy of the first sinusoid formant of the heart sounds in subjects with PAH reveals an organized pattern in heart sounds. The analysis of this pattern revealed a unique sound signature produced by the hypertensive pulmonary artery and right ventricle, which can be captured and used to diagnose PAH


“Responses Of EGLN1/VHL And HIF1AN/CBP: The Factual Oxygen Sensor Molecules At High-Altitude.”

Qadar Pasha
This study is designed to serve the objectives of (i) finding the association of HIF1AN and EGLN1 variants with HA adaptation and maladaptation, (ii) to find interactions between them and (iii) the various correlations between these two hydroxylases and other biomarkers like NO and ROS. Further, (iv) the methylation study will add to understanding the epigenetic role. 


2012


“Targeting Metabolism To Reverse RV Dysfunction In PAH: A Clinical Study From Molecule To Human.”

Yuchi Han
This project studied how the RV fails both by imaging it with radioactive glucose and fat metabolites, by cell studies and by a small trial of a drug called ranolazine that may have some benefit in oxygen starved muscle. New areas of interest in PH were pursued including a new class of RNA modulating nucleotides called microRNA, and stem cells were cultured from patients to get a better idea of basic cellular metabolic behavior. 


2011


“Mutation Analysis of Pulmonary Hypertension Breakthrough Initiative.” 

Micheala Aldred
Research includes mutational analysis of the genes BMPR2, ALK1, ENG and SMAD9, including sequencing of all coding regions and intron-exon boundaries, together with dosage analysis to detect larger genomic rearrangements.


"Pre-Clinical Support For The Development Of A Right Ventricular Assist Device (RVAD)" 

Circulite, Inc.
Research on modifying the existing design of the partial support LVAD as an RVAD for refractory heart failure in advanced pulmonary hypertension.


“Robyn Barst Pediatric Research and Mentoring Fund” 

Pulmonary Hypertension Association
Creation of a pediatric medical education of enduring value for pulmonary hypertension to honor Dr. Robyn Barst. Included in the project are CME accredited courses, case studies, the development of a pediatric resource center, an oral history of development of the field and a webinar series. All programs were integrated into PHA’s new Online University website, www.phaonlineuniv.org. 

"Pulmonary Vascular Research Institute"

A 5 year unrestricted grant to support the mission of this unique professional organization as it expands its educational, scientific, and global outreach in pulmonary vascular diseases.