Immunobiology of the normal and injured lung

项目摘要 成人肺在其复杂性和功能方面继续令人惊讶，从发现新的细胞类型到 对现有细胞和分子通路在动态平衡和非平衡状态下新功能的理解 受伤。在当前的新冠肺炎大流行期间，肺部生物学从未像现在这样受到如此关注 迫切需要肺免疫生物学的基础研究来推动治疗发展，以解决 在急性肺损伤和急性呼吸窘迫综合征(ARDS)中未得到满足的需求。在过去15年里，我们 我在先天免疫和血液学的交叉点上研究了肺部生物学，这是 NHLBI的任务是。促进了小鼠肺活体成像技术的发展和 先进的移植技术，我们在这方面取得了根本性的发现，在正常和 损伤的肺，将作为本应用中拟议研究的基础。为了增进我们的理解 在肺损伤机制方面，我们将使用已建立的无菌和病原体诱导的肺损伤模型和现有的 ARDS生物库是在之前的资助下开发的，以继续我们对血小板贡献的研究， 中性粒细胞和中性粒细胞胞外陷阱(NETs)与疾病发病机制有关。这些研究将包括 抗体引发输血或实体器官移植后肺损伤的机制 包括开发新的损伤模型和治疗靶向。在这个主题下，我们将继续 成人肺内不同类型巨核细胞及其在血小板生物发生和肺组织中作用的研究 豁免权。我们将通过测试人类肺的假设来探索肺的造血潜力 含有大量的造血祖细胞，这些造血祖细胞可能对 动态平衡与损伤及造血干细胞移植后。加州大学旧金山分校的环境包括 已建立的合作关系和先进核心的可获得性，将使这一肺生物学计划能够 在这一筹资机制下加速发现，推动该领域向前发展。

Project Summary The adult lung continues to amaze in terms of its complexity and function from the discovery of new cell types to the understanding of new functions of existing cells and molecular pathways operating during homeostasis and injury. Never has lung biology received more attention as during the current COVID-19 pandemic where fundamental studies in lung immunobiology are urgently needed to advance therapeutic development to address unmet need in acute lung injury and the acute respiratory distress syndrome (ARDS). For the past 15 years, we have studied lung biology at the intersection of innate immunity and hematology, which are core components of the NHLBI’s mission. Facilitated by technical development in the intravital imaging of the mouse lung and by advanced transplantation techniques, we have made fundamental discoveries in this area in the normal and injured lung that will serve as the basis of the proposed studies in this application. To advance our understanding of lung injury mechanisms, we will use established models of sterile and pathogen-induced lung injury and extant ARDS biorepositories developed under previous funding to continue our studies of the contribution of platelets, neutrophils, and neutrophil extracellular traps (NETs) to disease pathogenesis. These studies will include mechanisms by which antibodies trigger lung injury after blood transfusions or after solid organ transplantation including the development of novel models of injury and therapeutic targeting. Within this theme, we will continue studies on distinct populations of megakaryocytes in the adult lung and their roles in platelet biogenesis and lung immunity. We will explore the hematopoietic potential of the lung by testing the hypothesis that the human lung contains significant numbers of hematopoietic progenitors that may uniquely contribute to hematopoiesis in homeostasis and injury and after hematopoietic stem cell transplantation. The environment at UCSF includes established collaborations and accessibility to advanced Cores that will enable this program of lung biology to accelerate discoveries under this funding mechanism and move the field forward.