NHLBI Topics of Special Interest (TOSI)
HL-131: Developmental Pathways in the Pathogenesis of Adult Chronic Lung Diseases (R01)
To support mechanistic studies to understand the roles of developmental pathways in the pathogenesis of human adult chronic lung disease.
Purpose and Rationale of the Initiative
Recent genomic and gene expression data from multiple adult lung diseases, including idiopathic pulmonary fibrosis (IPF), emphysema, COPD, and pulmonary arterial hypertension, have shown a strong association of disease pathogenesis with disrupted developmental pathways, suggesting that the pathogenesis of these lung diseases involves the same basic machinery that regulates cell proliferation, specification, differentiation, and communication during normal development. For example, research supported by the Lung Genomic Research Consortium (LGRC) and Lung Tissue Research Consortium (LTRC) has found that transcripts associated with lung development are enriched in diseased lungs. In IPF lungs, developmental genes such as transcription factor families (fork-head box, twist1), and those in signaling pathways (Wnt, Shh) are significantly up-regulated, indicating normal developmental pathways regulating epithelium/mesenchyme differentiation and communication may be abnormally activated during disease.
However, the exact role of developmental genes in the pathogenesis and progression of adult lung diseases remains unknown and several questions need to be addressed, such as: Is the aberrant activation a causal factor or just an association? If there is a causal relationship, what are the underlying mechanisms? Are there strategies to correct or re-balance the disrupted pathways to reverse the pathophysiology? How can better therapeutic targets be identified, such as the context-specific downstream effectors in the pathways?
NHLBI is interested in supporting studies to answer these and other questions that will advance our understanding of the roles developmental pathways play in the pathogenesis of human, adult chronic lung disease. Investigators that have identified candidate developmental pathways or a network(s) of genes from genomic studies of adult lung disease are invited to submit applications under this TOSI. Projects combining both classic principles in genetics and embryology and novel, cutting-edge methodology including biochemical, imaging and systems approaches, are encouraged. Systems approaches to data analysis are also encouraged to identify additional components in the pathway/network. Proposals focusing only on a single gene may be less favorably viewed.
In addition, studies that use either human primary cell/tissue culture or model systems, or both, to test hypotheses related to developmental genes in the pathogenesis of human lung disease are encouraged. Studies to establish functional causality from the genes to defined phenotypes, to develop strategies to manipulate the pathways in vivo to re-gain tissue homeostasis and cellular functions, and to identify novel context-specific downstream targets are also relevant to this TOSI. Leveraging existing resources, including genomic and gene expression databases, human tissue repositories, and animal repositories, is further strongly encouraged as are team-oriented approaches that include experimental developmental biologists, -omics investigators, and pulmonary physician scientists.
Selected Research Examples
Some specific examples may include, but are not limited to:
- Use systems approaches to identify key regulatory networks that determine lung phenotypes in health and disease;
- Perturb development pathways in cultured human lung cells/tissues, develop downstream genomic signatures and compare to lung disease signatures;
- Study the lead genes in vivo with ability to manipulate gene expression with dose, time and tissue specificity;
- Roles of mis-expressed developmental genes in lung disease patients in lineage determination and cell plasticity;
- Apply principals of developmental genetics to identify modifiers as new, context-specific, targets in known pathways, and test those with new or existing interventions;
- Combine/compare forward genetics (unbiased, phenotype-driven approach to understand the trait) with patient genomic information.
Standard receipt dates apply as indicated in the parent RO1 FOA: PA-13-302 Research Project Grant (Parent R01).
Application and Submission Information
Investigators interested in developing applications for these topics are encouraged to submit investigator‐initiated R01 applications
under PA-13-302. At the beginning of the title, please include the following characters: HL-. In the first sentence of the abstract, please include the specialized code: HL-131.
Qing "Sara" Lin, Ph.D.
Lung Biology and Disease Branch
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Tel: (301) 435-0222
Last Updated: October 2013