Vallerie McLaughlin, M.D.
University of Michigan
Databank and Coordinating Center
The first aim of the DBCC is to structure an efficient and effective communication and data system for the network. The structure of the DBCC will include the principle and sub investigators, an Internal Advisory Committee, and the project management team. The Clinical Research Informatics Core of the DBCC has experience in with multiple technologies including ENGAGE, Velos, and the Honest Broker. The database will be designed with the input of the Steering Committee and the Research Advisory Committee of the CMREF.
Jerry Eu, M.D.
Duke University
Transplant and Preparation Center
Our Transplant and Preparation Center (TPC) will combine the expertise and resources of pulmonary hypertension, lung transplant and pathology programs at Duke to support the research efforts of Idiopathic Pulmonary Arterial Hypertension (IPAH) Research Network. In each of the past few years, approximately 3 out of 60 adult patients who underwent lung transplantation at Duke had IPAH. The multidisciplinary members in our TPC will procure explanted lungs and blood samples from IPAH and other patients during future lung transplant operations and prepare these tissues for studies designed to better understand the etiology and pathogenesis of IPAH.
Martin Zamora, M.D.
University of Colorado, Denver
Transplant and Preparation Center
Tissue Acquisition Procedure
The pathologist is contacted to request permission to cut the explanted lung as needed, as soon as it is ready. The OR staff is notified ahead of time of our plans to be in attendance. In the case of explant, the technician should set up, well before the lung is removed, in the adjacent OR room if it is available. The OR staff is instructed to keep the lung sterile/ RNAse-free in a blue lidded specimen container and on ice, if the technician can’t be there at the moment of explant. A Dewar flask is filled with liquid N2 and placed in a secure place in the work area. The appropriate sterile pack is opened, using sterile technique, in preparation for processing specimens. The pre-labeled containers are set up in a clean, convenient location, and their caps are loosened. Tissue grossing and sectioning is performed based on LTRC protocols. The hospital’s ‘Tissue Pathology Request’ is filled out – leaving room for quantifying size, the approximate percentage taken for the TPC study, and- for explants- the total pre-cut weight. The technician also puts their contact information on the form.
Marlene Rabinovitch, M.D.
Stanford University
Transplant and Preparation Center
Patient Population: Lungs removed at transplantation will be procured in collaboration with UCSF and University of Toronto. Those procured from UCSF will be prepared at Stanford and those from the University of Toronto will be prepared at that center. We anticipate 3-5 lungs a year for IPAH, 5-6 for secondary PAH (Eisenmenger’s), 5-6 for secondary PAH (chronic lung disease) and 5-6 matched non-PAH controls. Both Stanford and the University of Toronto have extensive databases from which clinical information (75 data points/patient at Stanford) can be retrieved. This will serve both for entry into the DCC as well as for future use by Network Investigators.
George Noon, M.D.
Baylor College of Medicine
Transplant and Preparation Center
Patients are referred to The Methodist Hospital, St. Luke's Hospital and Texas Children's Hospital for lung transplant evaluation. They undergo a thorough physical evaluation and testing, meet with pulmonologists, surgeons, transplant coordinators, and the transplant research coordinator. After their testing is complete, they are presented to the thoracic transplant patient selection committee. If the patient is deemed an acceptable candidate for pulmonary transplant, and has financial and social clearance, the transplant coordinators will list the patient with UNOS (United Network Organ Sharing). At each institution, the physicians and transplant coordinators have access to the lung transplant list. The patients name and diagnosis are included on the list. All patients on the transplant list with idiopathic pulmonary artery hypertension or primary pulmonary hypertension will be eligible to participate in the study.
Barbara Meyrick Ph.D.
Vanderbilt University
Transplant and Preparation Center
This application will initiate a Transplant and Preparation Center drawing on the transplant surgeries for IPAH that are carried out both at Vanderbilt University (VU) and Barnes-Jewish Hospital, Washington University.
Keith Wille, M.D.
University
of
Alabama
Transplant and Preparation Center
At UAB, we will establish a team to facilitate the rapid collection of lungs removed at transplant from patients with primary (idiopathic) pulmonary arterial hypertension (PPAH) and other pulmonary diseases which can be used as controls for the study of PPAH. To permit comparisons, equivalent tissue will be collected from the same areas of each lung and uniquely labeled as to site/source in the lung. Specifically, endothelial cells and smooth muscle cells will be collected for culture from arteries and separately from veins and transferred directly to the Cell Culture Facility. Arteries, veins, and supporting tissues will be dissected for molecular analysis at the gene expression level and proteomic analysis. Proteomic analysis also will include obtaining tissues to be fixed in various fixatives for immunohistochemical studies of protein expression and research involving in situ hybridization and real time quantitative PCR. Supporting lung tissues for studies in molecular biology will be collected and snap frozen at the collection site. These tissues will be transferred for processing and storage to the Tissue Processing Core at UAB.
Raymond Benza, M.D.
Allegheny General Hospital
Transplant and Preparation Center
The regional transplant center at Allegheny General Hospital (AGH) operates with the active participation of the Center for Organ Recovery and Education (CORE) to enhance the volume of successful transplant and normal tissue procurements for the PHBI consortium.
Peter Lloyd Jones, Ph.D.
The University of Pennsylvania
Center for Cell Studies
Abstract Idiopathic pulmonary arterial hypertension (IPAH) is an under-diagnosed disease for which there is no cure. At a structural level, remodeling of pulmonary arteries (PA) in severe PAH may result from selective death as well as proliferation of sub-sets of endothelial cells (ECs), hypertrophy and hyperplasia of vascular smooth muscle cells (SMCs), expansion of the adventitial fibroblast layer, (together with its associated vasa vasorum via neo-angiogenesis), recruitment of circulating inflammatory and EC precursors to the pulmonary vascular wall, and simultaneous catabolism and synthesis of specific components of the extracellular matrix (ECM). Despite the increase in knowledge concerning the etiology of IPAH, (e.g. the discovery of BMP type II receptor mutations in familial and sporadic forms of PAH, a more comprehensive characterization of normal and IPAH cells is needed in order to promote development of new diagnostics and therapies. To help accomplish this mission, the Penn CMREF IPAH Cell Center Core proposes to: (1) Acquire control and IPAH tissues and fluids; (2) Isolate control and IPAH lung vascular, circulating cells and fluids; (3) Phenotype control and IPAH lung vascular, circulating cells and fluids; (4)(5) Immortalize control & IPAH cells using telomerase; (6) Distribute cells and fluids to the CMREF/IPAH network; (7) Define an IPAH plasma proteome and IPAH cell signalome; (8) Prepare material for network partners & interact with other Investigators; (9) Generate, coordinate and manage cell- and fluid-derived data. The schematic below summarizes our proposed activities. Test, Preserve & Bank Cells;
Mark W. Geraci, M.D.
University of Colorado, Denver
Center for Geonomics
To provide excellence in genomic analysis for CMREF IPAH researchers.
Rationale: Methods for genomic analysis have proven powerful tools for identification of potential new pathobiology, biomarkers, and drug targets. The field of genomics and its associated technologies is rapidly evolving. Initially, the use of expression arrays became a powerful avenue for hypothesis generation and discovery. More recently, the ability to perform high-throughput SNP analysis has also enabled investigators to explore the genome in disease states. With such density of SNPs on an array, it is now possible to consider large-scale association studies, such as was done in patients with esophageal cancer. Complex traits can also be examined, as has been performed in inbred murine strains. Indeed, SNP analysis has been shown to increase information content compared to traditional microsatellite approaches. With the density and content of these arrays increasing, the ability to perform powerful association studies and examining quantitative trait loci should possible. Affymetrix currently has available a 100k SNP set, with plans to release a 500k set within the year. As in the early days of microarray expression analysis, handling such data has proven to be complex, but newer algorithms, some freely available in the public domain, are becoming established. As a further step to improve statistical power, clusters of SNPs can be evaluated en block, as haplotypes, which reduces the numbers of statistical tests performed and lessens the chance of type I errors due to false positives.
Allen D. Everett, M.D.
Johns Hopkins Hospital
Center for Proteomics
Proteomics Core Goal
We have assembled a unique and experienced group of established scientists to form a center for projects to catalogue the serum proteome in patients with pulmonary hypertension in an effort to identify biomarkers of disease.
William E. Grizzle, M.D., Ph. D.
University of Alabama at Birmingham
Center for Tissue Processing
The Tissue Collection and Banking Facility (TCBF) at the University of Alabama at Birmingham (UAB) has extensive experience in the collection, processing, storage, and distribution of human tissue samples for research. This facility has provided prospective procurement services to UAB investigators since 1978, and has provided services to investigators throughout the United States and Canada as the Southern Division of the NCI sponsored Cooperative Human Tissue Network (CHTN) since 1987. In addition, this facility has provided biorepository banking services to a number of projects at UAB, including the Breast, Ovarian, and Pancreatic SPOREs, the Early Detection Research Network, the Genitourinary Bank, the UAB Liver Center, and the Skin Disease Research Center.
Barbara Meyrick Ph.D.
Vanderbilt University
Center for Proteomics
Proteomic Approach to Unravelling the Pathogenesis of IPAH.
Diverse germline heterozygous mutations in the bone morphogenetic protein receptor type II (BMPR2) gene have been demonstrated in the majority of patients with familial pulmonary artery hypertension (FPAH) and approximately 25% sporadically affected subjects (IPAH). Since not all persons with mutations in BMPR2 develop the disease, our first hypothesis is that full expression of FPAH is accompanied by alterations in expression of one or a series of proteins as well as mutations in the BMPR2 gene.
Jack Olson, M.D.
University of Southern Alabama
Center for Cell Studies
Research Plan – Determine whether polyamines are rationale targets for PAH drug therapy. Polyamines (putrescine, spermidine and spermine) are essential for cell survival and proliferation. They regulate many functions including cell division, apoptosis, gene transcription and, synthesis of DNA, RNA and proteins. Polyamines are key nodes for integrating and regulating multiple signals, including c-myc, Smad and p38MAPK signals.
CMREF is proud to announce that as of January 2006, we have established our PHBI (Pulmonary Hypertension Breakthrough Initiative) Research Network. Please click here to view the names of those recipients who have been awarded a research grant.
