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:
  • 金额:
    $ 94.5万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)

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Michael J Holtzman其他文献

Distinct characteristics of T cell rolling and adhesion in splenic versus lymph node vessels
  • DOI:
    10.1016/s0091-6749(02)82116-9
  • 发表时间:
    2002-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Mitchell H Grayson;Michael J Holtzman;David D Chaplin
  • 通讯作者:
    David D Chaplin

Michael J Holtzman的其他文献

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{{ truncateString('Michael J Holtzman', 18)}}的其他基金

Defining and Controlling Airway Disease
定义和控制气道疾病
  • 批准号:
    10579266
  • 财政年份:
    2019
  • 资助金额:
    $ 94.5万
  • 项目类别:
Defining and Controlling Airway Disease
定义和控制气道疾病
  • 批准号:
    9889988
  • 财政年份:
    2019
  • 资助金额:
    $ 94.5万
  • 项目类别:
TREM2 AND AIRWAY DISEASE
TREM2 和气道疾病
  • 批准号:
    9335933
  • 财政年份:
    2016
  • 资助金额:
    $ 94.5万
  • 项目类别:
IL-33 AND EXCESS MUCUS PRODUCTION
IL-33 和粘液分泌过多
  • 批准号:
    9223736
  • 财政年份:
    2014
  • 资助金额:
    $ 94.5万
  • 项目类别:
IL-33 AND EXCESS MUCUS PRODUCTION
IL-33 和粘液分泌过多
  • 批准号:
    8790768
  • 财政年份:
    2014
  • 资助金额:
    $ 94.5万
  • 项目类别:
Preclinical Development of an Anti-Mucus Drug
抗粘液药物的临床前开发
  • 批准号:
    8748733
  • 财政年份:
    2014
  • 资助金额:
    $ 94.5万
  • 项目类别:
INTERFERON SIGNAL ENHANCERS AS ANTIVIRAL THERAPEUTICS
干扰素信号增强剂作为抗病毒治疗
  • 批准号:
    8697863
  • 财政年份:
    2014
  • 资助金额:
    $ 94.5万
  • 项目类别:
IL-33 AND EXCESS MUCUS PRODUCTION
IL-33 和粘液分泌过多
  • 批准号:
    8632665
  • 财政年份:
    2014
  • 资助金额:
    $ 94.5万
  • 项目类别:
Preclinical Development of an Anti-Mucus Drug
抗粘液药物的临床前开发
  • 批准号:
    9317525
  • 财政年份:
    2014
  • 资助金额:
    $ 94.5万
  • 项目类别:
IL-33 AND EXCESS MUCUS PRODUCTION
IL-33 和粘液分泌过多
  • 批准号:
    8996714
  • 财政年份:
    2014
  • 资助金额:
    $ 94.5万
  • 项目类别:

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