Role of bone marrow cells in pathogenesis and therapy of heritable pulmonary arterial hypertension

PI：Hamid，Rizwan，MD，Ph.D. 骨髓细胞在遗传性肺动脉高压发病及治疗中的作用 项目摘要 该项目的长期目标是设计更好的常染色体显性遗传的治疗方案。 肺动脉高压（HPAH）是一种罕见的肺部遗传性疾病。HPAH是一种致命的疾病， 有效的治疗选择。HPAH的主要病因是BMPR 2基因突变。HPAH是一种 以累及血管内皮的小肺动脉重塑为特征的进行性致死性疾病 和平滑肌细胞，其闭塞血管腔。这些重塑的血管 然而，我们并不完全了解骨髓源性细胞（BMC）的作用。 这些细胞在HPAH发病机制中的确切作用。我们最近发现Bmpr 2突变体的移植 BMC在对照（Ctrl）小鼠中引起PAH，而在Bmpr 2突变小鼠中移植Ctrl BMC导致PAH。 减少PAH。这些数据表明，与以前的想法相反，BMC可能有一个因果关系， 在PAH中的作用然而，我们不知道总BM群体中重要的关键细胞类型， 从机制上知道肺中的谱系定向BMC如何促成HPAH，以及更多， 重要的是这些细胞在逆转HPAH肺表型中的治疗潜力的程度。我们 假设特定突变BMC群体引起HPAH，且特定WT BMC在HPAH中起作用， 疾病衰减和恢复。我们建议在3个具体目标中探索这些假设。1)测试 假设特定的BMC群体在HPAH中具有因果作用。2)研究假设BM 细胞移植可以预防或逆转已建立的HPAH。3)确定血统 定向的BMC群体有助于HPAH的发病机制。我们的提案位于 肺生物学和BMC生物学，是肺生物学家，干细胞生物学家和 临床医生，并将产生协同效应，这是不容易匹配的一个单一的研究者。的理由 对于拟议的研究是，更好地了解BMCs在HPAH中的作用不仅会导致 显著提高了对疾病发病机制的认识，也提高了对BMC是否是一种有用的治疗方法的认识。 选择-考虑到HPAH的有效长期治疗选择严重 有限公司虽然这一建议是翻译的范围，它也提出了一个创新的范式， 干细胞生物学和肺生物学我们期望：1）更好地了解 BMC在HPAH中的作用; 2）确定BMC在HPAH中的全部治疗潜力。

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.