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Defining and Controlling Airway Disease

定义和控制气道疾病

基本信息

批准号：
10352375
负责人：
Michael J Holtzman
金额：
$ 94.5万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-08 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10352375
关键词：
3-Dimensional Address Airway Disease Asthma Attenuated Back Cause of Death Cell Differentiation process Cell Proliferation Cell Separation Cell physiology Cells Cellular biology Charge Chromatin Chronic Obstructive Pulmonary Disease Data Disease Drug Design Environment Epithelial Cells Extramural Activities Functional disorder Genomics Goals Homeostasis Human Immune Immune response Individual Infection Interruption Lead Link Lung Medical Research Mentors Mission Mitotic Molecular Molecular Target Morbidity - disease rate Mucous body substance National Heart, Lung, and Blood Institute Pathogenesis Pathway interactions Phosphotransferases Population Prevention therapy Production Proteomics Public Health Research Research Personnel Resources Role Scientist Structure Technology Therapeutic Intervention Tissues Training Transplantation Universities Validation Viral Work airway epithelium airway repair base career development cell behavior cellular targeting chronic respiratory disease effective therapy epithelial stem cell innovation lung development mortality mouse model multidisciplinary novel strategies porcine model programs respiratory virus response to injury stem cells translational impact water channel

项目摘要

Abstract Airway epithelial cells were originally regarded as an inert barrier to the environment, but are now viewed as key regulators of the response to injury and infection with a critical role in airway repair that mimics lung development. Furthermore, altered behavior of this cell population is central to the pathogenesis of common airway diseases such as asthma and COPD, making it essential to understand the mechanisms responsible to normal and abnormal programming of this cell population. My research program is thematically focused on airway epithelial cell programming with the goal of characterizing the molecular basis of airway epithelial cell function and dysfunction for airway homeostasis versus disease. Our work to date has contributed to new paradigms in airway epithelial cell biology, including the first evidence of an active role for airway epithelial cells in directing the immune response towards airway disease and now the first data for an elusive airway progenitor epithelial cell (APEC) population that can be respiratory-virus activated to orchestrate disease and thereby explain how a transient infection could lead to long-term disease. Building on this work, we will focus going forward on creating a new concept for tissue homeostasis versus disease based on a set of transformative paradigms where progenitor cell reprogramming switches a normal airway epithelial barrier to one dominated by mucus production and the consequent morbidity and mortality of airway disease. We will provide the first definition of the key population of airway progenitor epithelial cells and the first mechanisms for how these cells are switched to disease-producing cells, incorporating unprecedented roles for: (1) endogenous viral, water channel, and nucleokine control of mitotic chromatin in these cells; and (2) an exogenous danger loop from these cells to immune cells and back to drive a distinct progenitor-cell kinase now targeted with structure-based drug design to interrupt mucus production. Translational impact also derives from new mouse and pig models and validation in humans with comparable disease. This substrate is combined with new approaches to cell isolation, 3D manipulation, and transplantation based on targets identified from genomic and proteomic analyses. Each of the individual approaches within the overall Program is charged to investigators in training to integrate scientific career development into the mission for medical research and discovery. In addition, the Program relies on vital and sophisticated input from senior pulmonary scientists for additional mentoring and cutting-edge approaches and innovations. The Program also incorporates the wider University and extramural resources to deploy multidisciplinary technologies with outstanding collaborators. Together, we expect our Program to provide a transformative paradigm for true progenitor epithelial cell programming and its role in cell proliferation and differentiation, including skewing towards mucous cell formation and excess mucus production that is central to airway disease. We also fully expect that our studies will identify the first tractable cellular and molecular targets and corresponding therapeutic intervention to attenuate airway disease, consistent with the mission of NHLBI.

摘要