PI: Hamid, Rizwan, MD, Ph.D. Role of bone marrow cells in pathogenesis and therapy of heritable pulmonary arterial hypertension PROJECT SUMMARY The long-term objective of this project is to devise better treatment options for autosomal dominant Heritable Pulmonary Arterial Hypertension (HPAH), a rare genetic disorder of lungs. HPAH is a lethal disorder without effective treatment options. The predominant cause of HPAH is mutations in BMPR2 gene. HPAH is a progressive, fatal disease characterized by small pulmonary arterial remodeling involving vascular endothelium and smooth muscle cells, which obliterate the vascular lumen. These remodeled vessels are always surrounded by large numbers of bone marrow-derived cells (BMC) however, we do not fully understand the exact role of these cells in HPAH pathogenesis. We have recently shown that transplant of Bmpr2 mutant BMCs caused PAH in control (Ctrl) mice and transplant of Ctrl BMC in Bmpr2 mutant mice resulted in attenuation of PAH. These data indicate that counter to what was previously thought, BMCs may have a causal role in PAH. However we do not know the key cell type in the total BM population that is important, we do not know mechanistically how the lineage-committed BMC in the lungs contribute to HPAH and further more and importantly the extent of the therapeutic potential of these cells in reversing the HPAH lung phenotype. We hypothesize that specific mutant BMC populations cause HPAH, and specific WT BMCs play a role in disease attenuation and recovery. We propose to explore these hypotheses in 3 specific aims. 1) Test the hypothesis that specific BMC populations have a causal role in HPAH. 2) Investigate the hypothesis that BM cell transplantation can prevent or reverse established HPAH. 3) Determine the mechanism by which lineage committed BMC populations contribute to the pathogenesis of HPAH. Our proposal sits at the intersection of lung biology and BMC biology and is a collaborative effort between lung biologists, stem-cell biologists, and clinicians and will produce a synergistic effect that is not easily matched by a single investigator. The rationale for the proposed research is that better understanding of the role of BMCs in HPAH will lead to not only significantly improved insight into disease pathogenesis but also whether BMCs are a useful therapeutic option?an important point considering that effective long-term treatment options for HPAH are severely limited. While this proposal is translational in scope it also presents an innovative paradigm that integrates stem cell biology with lung biology. It is our expectation that we will: 1) develop a better understanding of the role of BMC in HPAH; 2) determine the full therapeutic potential of BMCs in HPAH.

Public Health Relevance

PI: Hamid, Rizwan, MD, PhD Role of bone marrow cells in pathogenesis and therapy of heritable pulmonary arterial hypertension PROJECT NARRATIVE Poor prognosis, treatment and survival remain major problems in patients with Heritable Pulmonary Arterial Hypertension (HPAH). This project examines the role of bone marrow derived cells in pathogenesis and potentially therapy in PAH, using novel hypothesis, state-of-the-art mouse models, and stem cell transplantation approaches. The end result will be enhanced understanding of the how different populations of bone marrow cells can contribute to both disease and therapy in PAH.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL136748-04
Application #
9934000
Study Section
Therapeutic Approaches to Genetic Diseases Study Section (TAG)
Program Officer
Xiao, Lei
Project Start
2017-04-01
Project End
2021-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232