AIRWAY SMOOTH MUSCLE MODULATES INFLAMMATION IN ASTHMA

  • Panettieri, Reynold (PI)
  • Pure, Ellen Pure' (PI)
  • Fish, James (PI)
  • Benovic, Jeffrey (PI)
  • Pure, Ellen (PI)
  • Peters, Stephen (PI)

Project Details

Description

DESCRIPTION OF PROPOSED PROGRAM
This proposal is an interdisciplinary effort that
focuses on defining the cellular and molecular mechanisms by which airway
smooth muscle (ASM) orchestrates and perpetuates airway inflammation. The
central hypothesis states that synthetic responses of ASM modulate airway
inflammation and remodeling in asthma. Although many studies have identified
mechanisms that regulate inflammatory cell trafficking and activation, few
have asserted a role for myocytes in modulating airway inflammation. ASM
synthetic responses are defined as secretion of cytokines, chemokines, growth
factors and expression of cell adhesion molecules and matrix components. To
test our central hypothesis, four Projects and three Core Units are proposed.
Project 1 will characterize the molecular signaling pathways that regulate
cytokine-induced synthetic responses in human ASM. Preliminary data
demonstrate that selective inhibition of pathways activated by IL-1beta and
TNF-alpha has differential effects on the modulation of synthetic functions by
these cytokines. These findings support a central hypothesis that cytokines
regulate ASM synthetic functions through the coordinated activation of diverse
signaling events. Recently established techniques for the transfection and
microinjection of human ASM cells will enable delineation of the precise
molecular mechanisms by which cytokines activate these pathways. Project 2
will determine how cell-matrix receptors such as CD44 promote airway
inflammation, remodeling and airway hyperresponsiveness (AHR) by altering ASM
function. Allergen-induced AHR is markedly inhibited in mice treated with
antibodies that inhibit CD44 and in CD44 null mice. However, IgE production
and leukocyte recruitment were unaffected in these animals. These data support
the hypothesis that local CD44-matrix interaction regulates AHR. Using
genetically manipulated mice and segmental allergen challenge (SAC) models,
the relative contribution of CD44 expression on hernatopoetic cells versus
lung cells and the molecular basis by which CD44 modulates AHR and airway
remodeling will be determined. Project 3 will define the role of G protein
coupled receptor (GPCR) trafficking and signaling in modulating inflammatory
responses of ASM. GPCRs play a critical role in regulating multiple ASM
functions including contraction, relaxation, and synthetic function. The
dynamic regulation of GPCRs results in their movement or trafficking within
the cell. Recent studies support the hypothesis that such movement is
controlled by multiple mechanisms and that GPCR trafficking plays an important
role in regulating signaling. A comprehensive series of studies using ASM
cultures and transgenic mouse models are proposed to determine the mechanisms
by which GPCR localization and trafficking regulate ASM signaling and
function. Project 4 will study the mechanisms by which epithelial-ASM or
-fibroblast interactions foster airway remodeling and inflammation. Cultured
epithelial cells from asthmatics manifest a pro-inflammatory, fibrogenic
phenotype towards ASM cells and fibroblasts. These data support the hypothesis
that epithelial cells from asthmatics secrete substance(s) that act on
fibroblasts and ASM to promote the structural airway changes in asthma. Using
SAC and a novel epithelial cell culture model, the factors that promote
fibrogenesis and the signaling pathways they activate in mesenchymal cells
will be determined. Three Core Units support four Projects. Core A will
perform murine physiology, histology, cytology and will establish cell lines
derived from wild type and transgenic mice. Core B will supply the Projects
with physiological studies and clinical specimens from asthmatics and normals.
Core C will provide administrative and fiscal support. Using hypothesis-driven
molecular studies of genes, proteins, cells, tissues, animal models and
asthmatic patients, this interdisciplinary program will also provide new
insight into the pathogenesis and treatment of asthma.
StatusFinished
Effective start/end date9/30/016/30/10

Funding

  • National Institutes of Health
  • National Institutes of Health: $1,925,920.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $1,980,319.00
  • National Institutes of Health: $1,958,151.00
  • National Institutes of Health
  • National Institutes of Health: $1,866,784.00
  • National Institutes of Health: $2,039,422.00
  • National Institutes of Health

ASJC

  • Medicine(all)

Fingerprint Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.