Extramural Research Pulmonary Arterial Hypertension. James P. Kiley, M.S., Ph.D. June 20, 2008

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1 Extramural Research Pulmonary Arterial Hypertension James P. Kiley, M.S., Ph.D. June 20, 2008

2 Outline Overview DLD Programs in PH NHLBI Strategic Plan Future Directions What s new at NIH

3 Current Extramural Funding Division of Lung Diseases FY 2007 Number of Projects = 1,353; Total Funds = $598 Million DLD Lung Cell/ Vascular Biology 10.6 % Pulmonary Hypertension Currently: 74 Investigator-initiated Grants ($74M) Basic Clinical

4 Basic PAH Research Molecular Genetic Cellular

5 PAH Translational Research Response of pulmonary vasculature to hypoxia, vascular inflammation, pharmacogenetics of IPAH, role of the immune system, SCCOR..

6 Pulmonary Arterial Hypertension Translational Research Rho Kinase Inhibitors Prostacylin Pathway Statins Endothelin Pathway Cell Based Rx Nitric Oxide Pathway In the pipeline Six Approved Rx

7 A Phase II Clinical Trial of Aspirin and Simvastatin in PAH Aspirin 81 mg Simvastatin 40 mg Steven M. Kawut, M.D., M.S. Columbia University, NY, NY Reda E. Girgis, M.B., BCh. Johns Hopkins University, Baltimore, MD (Funded by National Heart, Lung and Blood Institute grant HL082895)

8 Sildenafil Trial of Exercise Performance in IPF Purpose: To determine if sildenafil will improve exercise performance and quality of life in patients with idiopathic pulmonary fibrosis (IPF) Design: Double-blind, placebo-controlled safety and efficacy study in patients with a confirm diagnosis of IPF

9 Mapping to the NHLBI Strategic Plan Pharmaco Genetics Networks Markers SCCOR EDU GWAS Form Function Cause Cures

10 Where Are We Going? Multidisciplinary Approach to Lung Diseases Form Function Cause Cures Genetic - Environmental Basis of Disease (in Developmental Context) Disease Modifying Therapy Personalized Medicine Disease Pathogenesis Molecular Diagnostics biomarkers imaging Improved Health Care Delivery

11 How Do We Get There? Post-genomic pathogenetic research requires better phenotyping. Personalized medicine requires molecular characterization of disease in the individual patient. Preventive approaches require early detection of the disease process. Application of new knowledge would be accelerated by better intermediate outcome measures for use in clinical research.

12 Understanding the lung at molecular levels will lead to better diagnosis/prognosis, prevention, and cure of lung diseases. Stage 1 Molecular Parts Protein Glycomics mrnas ncrna 1. mirna 2. pirna 3. trna 4. rrna 5. snrna 6. snorna 7. grna 8. metabolites DNA Epigenetics Stage 2 Gene Ontology Molecular function Families Stage 3 Biological Pathways Processes Stage 4 Network Systems Approaches -OMCS Model Organism System Biology

13 Molecular Phenotyping for PAH? Biomarkers BMPR2 noncarriers BMPR2 carriers Genomics Sztrymf: Am J Respir Crit Care Med Jun 15;177(12):

14 Change in 6MWD (meters) Current developments in pharmacogenomics ET-1 polymorphism (End1K198N PM; Exon 5) and 6MWD in 432 PAH patients treated with endothelin antagonists Pts with the TT genotype showed a 50.4m decline relative to the TG and GG genotypes (p=0.041) TT End1K198N Genotype TG/GG Mean (diamond), median, quartiles +/- 1.5 IQR R. Benza et. al. Am J Resp Crit Care Med 2008; 177: A258

15 Molecular Phenotypes for Lung Diseases RFA-HL eqtl Gene Expression Stimulate research that will define or subcategorize human lung diseases at a molecular level enabling early diagnosis, prognosis, and personalized treatment Encourage the integration of data from other omics approaches (e.g., genomics, epigenomics, etc.) to reinforce or validate findings from RNA expression. Share data with the broad scientific community.

16 Early Origins of Lung Disease Genes and Gene Networks Environmental exposures Infant Age/Developmental Stage Programming of lung structure and function Regulation of innate immunity Disease phenotypes PH, asthma, CF

17 Developmental Origins of Altered Lung Physiology and Immune Function (RFA-HL08-009) Mechanistic studies to increase understanding of how the pre-and postnatal environments affect the developing lung and immune system simultaneously Requires collaboration between pulmonary and immunology experts Human subjects component required

18 NHLBI Progenitor Cell Biology Consortium Planning Award (R03) Department of Health and Human Services Issuing Organization National Heart, Lung, and Blood Institute ( Participating Organizations National Institutes of Health (NIH), ( Components of Participating Organizations National Heart, Lung, and Blood Institute (NHLBI/NIH) ( Title: NHLBI Progenitor Cell Biology Consortium Planning Awards (R03) Request for Applications (RFA) Number: RFA-HL

19 PH Co-Morbidities HIV Sleep COPD Heart Disease PH Scleroderma CF Sickle Cell

20 Source: NY Times System Medicine

21 Future Directions Genomics and Personalized Medicine Stem Cells and Regeneration Early Origins of Lung Diseases Others Co-Morbidities Right Ventricle Emerging technologies Nanobiology and 3 D Tissue Engineering

22 to support research that focuses on the interaction or relationship between the right ventricle and the lungs in both health and disease to stimulate research that will provide a more complete and clear picture of the mechanisms of right heart failure associated with chronic lung diseases. R01 applications Jan 2007-December

23 What s New at NIH? Enhancements to Peer Review Policy on Data Sharing for Genome- Wide Association Studies Public Access Policy Transformative R01 Program