Immunobiology of the normal and injured lung

正常和受损肺的免疫生物学

• 批准号: 10353875
• 负责人: MARK ROBERTS LOONEY
• 金额: $ 56.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2028-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10353875
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Adult; Amaze; Antibodies; Area; Attention; Biogenesis; Biology; Blood Platelets; Blood Transfusion; COVID-19 pandemic; Cells; Collaborations; Complex; Development; Disease; Environment; Funding; Funding Mechanisms; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Home; Homeostasis; Human; Immune; Immune System Diseases; Immune response; Immunity; Immunobiology; Infection; Injury; Lung; Lung diseases; Megakaryocytes; Mission; Modeling; Molecular; Mus; National Heart, Lung, and Blood Institute; Natural Immunity; Organ Transplantation; Pathogenesis; Pathway interactions; Population; Role; Solid; Sterility; Techniques; Testing; Tissues; Transplantation; biobank; cell type; extracellular; intravital imaging; lung injury; neutrophil; novel; novel strategies; pathogen; programs; response; therapeutic development; therapeutic target

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.

项目概要 从新细胞类型的发现到成体肺的复杂性和功能不断令人惊叹 了解现有细胞的新功能和在稳态过程中运行的分子途径 受伤。肺部生物学从未像当前的 COVID-19 大流行期间那样受到如此多的关注 迫切需要肺免疫生物学的基础研究来推进治疗方法的开发，以解决 急性肺损伤和急性呼吸窘迫综合征（ARDS）的需求未得到满足。过去15年，我们 研究了先天免疫和血液学交叉领域的肺生物学，这是肺的核心组成部分 NHLBI 的使命。小鼠肺部活体成像技术的发展以及 先进的移植技术，我们在正常和 受伤的肺部将作为本申请中拟议研究的基础。为了增进我们的理解 为了研究肺损伤机制，我们将使用已建立的无菌和病原体引起的肺损伤模型以及现有的肺损伤模型。 ARDS 生物储存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（NET）对疾病发病机制的影响。这些研究将包括 输血或实体器官移植后抗体引发肺损伤的机制 包括开发新型损伤模型和治疗靶向。在这个主题下，我们将继续 对成人肺中不同巨核细胞群及其在血小板生物发生和肺中的作用的研究 免疫。我们将通过检验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，可能对造血有独特的贡献 稳态和损伤以及造血干细胞移植后。 UCSF 的环境包括 建立了合作关系并获得了先进的核心，这将使该肺生物学项目能够 在这一资助机制下加速发现并推动该领域向前发展。