Project Details

Description

DESCRIPTION (provided by applicant): The goal of this proposal is to define the molecular signaling processes by which interferons (IFNs) inhibit basal and mitogen-induced growth of human airway smooth muscle (ASM) cells. This question is critical to understanding the pathogenesis of severe asthma, which is characterized by increased ASM mass and hyperplasia, and to developing new therapeutic approaches to abrogate myocyte hyperplasia. ASM growth induced by mitogens requires activation of p21 Ras, p60Src, phosphatidylinositol 3-kinase (PI3K) and S6K1. The Pl's studies show that IFN( and IFN( profoundly inhibit ASM growth while decreasing retinoblastoma (Rb) phosphorylation and increasing IFI 16 expression, key steps in regulating cell cycle progression. In vivo studies showed ASM constitutively expresses IFN( and autocrine IFN(, which activates JAK/STAT pathways, inhibited mitogen/cytokine-induced growth in vitro. The central hypothesis of this proposal states that basal, cytokine- and mitogen-induced ASM cell proliferation is inhibited by the autocrine secretion of IFNb in a JAK/STAT-and IFI 16-dependent manner. To test these hypotheses, in Aim 1 mitogen-induced ASM growth and activation of Src, PI3K and S6K1 in the presence and absence of IFNb will determine whether inhibition of these signals mediates IFNb growth effects. Studies using ASM transfected with mutant cDNA constructs or using siRNA knockdown will define whether JAK/STAT activity or IFI 16 expression is necessary and sufficient to inhibit myocyte growth. In Aim 2, abrogation of constitutive IFNb using siRNA, mutant cDNA constructs or ASM cells derived from IFNb -/- mice will determine whether abrogating constitutive IFN( promotes ASM growth. In Aim 3, the use of novel transgenic models that express GFP, that lack IFNb or overexpress PDGF exclusively in smooth muscle will characterize whether expression of IFNb in vivo is necessary and sufficient to regulate ASM hyperplasia induced by allergen or PDGF.Description
StatusFinished
Effective start/end date9/5/057/31/10

Funding

  • National Institutes of Health: $427,086.00
  • National Institutes of Health: $413,921.00
  • National Institutes of Health: $404,954.00
  • National Institutes of Health: $452,496.00

ASJC

  • Medicine(all)

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