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

派：哈米德，里兹万，医学博士，博士。 骨髓细胞在遗传性肺动脉高压发病和治疗中的作用 项目总结 该项目的长期目标是设计出更好的常染色体显性遗传性疾病的治疗方案 肺动脉高压(HPAH)，一种罕见的肺部遗传性疾病。HPAH是一种致命的疾病，如果没有 有效的治疗选择。BMPR2基因突变是引起HPAH的主要原因。HPAH是一个 以累及血管内皮细胞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，使血管管腔闭塞。这些改装的血管总是 然而，在大量骨髓来源的细胞(BMC)的包围下，我们并不完全了解 这些细胞在HPAH发病机制中的确切作用。我们最近发现Bmpr2突变体的移植 BMCs引起对照(Ctrl)小鼠的PAH和Ctrl BMC在Bmpr2突变小鼠体内的移植导致 多环芳烃的衰减。这些数据表明，与之前所认为的相反，BMC可能有一个因果关系 在PAH中的作用。然而，我们不知道在整个骨髓群体中哪种关键细胞类型是重要的，我们不知道 从机制上了解肺中与血统有关的BMC如何对HPAH做出贡献，以及更多 重要的是，这些细胞在逆转HPAH肺表型方面的治疗潜力的程度。我们 假设特定突变的BMC群体导致HPAH，并且特定的WT BMC在 疾病消退和康复。我们建议从三个具体目标来探讨这些假说。1)测试 假设特定的BMC群体在HPAH中起因果作用。2)调查BM的假设 细胞移植可以预防或逆转已建立的HPAH。3)确定血统的机制 承诺的BMC群体参与了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 并将产生单一研究人员难以比拟的协同效应。其基本原理是 因为拟议的研究是，更好地理解骨髓细胞在HPAH中的作用将不仅导致 显著提高了对疾病发病机制的洞察，也提高了骨髓细胞是否是一种有用的治疗方法 选择-考虑到HPAH的有效长期治疗选择严重 有限的。虽然这一提议在范围上是翻译的，但它也提出了一种创新的范式，它将 干细胞生物学与肺生物学。我们的期望是：1)更好地了解 BMC在HPAH中的作用；2)确定BMCs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.