Immunobiology of the normal and injured lung

项目摘要 成年人的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， 了解现有细胞的新功能和在体内平衡过程中运作的分子途径， 损伤在当前的COVID-19大流行期间，肺部生物学从未受到如此多的关注， 迫切需要肺免疫生物学的基础研究来推进治疗开发， 急性肺损伤和急性呼吸窘迫综合征（ARDS）的未满足需求。在过去的15年里，我们 在先天免疫和血液学的交叉点上研究了肺生物学，这是 NHLBI的使命。通过小鼠肺活体成像的技术发展以及 先进的移植技术，我们在这一领域取得了基本的发现， 受伤的肺，这将作为本申请中提出的研究的基础。为了增进我们对 肺损伤机制，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存的 在先前的资助下开发的ARDS生物储存库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（NET）与疾病发病机制的关系。这些研究将包括 输血后或实体器官移植后抗体引发肺损伤的机制 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 成人肺巨核细胞的不同群体及其在血小板生成和肺功能中的作用 免疫力我们将通过检验人类肺部 含有大量的造血祖细胞，这些造血祖细胞可能独特地有助于造血， 稳态和损伤以及造血干细胞移植后。UCSF的环境包括 建立了合作和先进的核心，这将使这个计划的肺生物学， 在这一资助机制下加速发现并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.