Title page for ETD etd-05072009-114808


Type of Document Master's Thesis
Author Fang, Youjia
Author's Email Address youjia@vt.edu
URN etd-05072009-114808
Title The Novel Role of Interleukin-1 Receptor-Associated Kinase 1 in the Signaling Process Controlling Innate Immunity and Inflammation
Degree Master of Science
Department Biology
Advisory Committee
Advisor Name Title
Li, Liwu Committee Chair
Li, Jianyong Committee Member
Xing, Jianhua Committee Member
Keywords
  • CREB
  • IRS-1
  • GSK3β
  • insulin resistance
  • Akt
  • TLRs
  • IRAK-1
Date of Defense 2009-05-05
Availability unrestricted
Abstract
Obesity-induced chronic inflammation plays a key role in the pathogenesis of insulin resistance and the metabolic syndrome. Proinflammatory cytokines can cause insulin resistance in adipose tissue, skeletal muscle and liver by inhibiting insulin signaling transduction. Interleukin-1 receptor-associated kinase-1 (IRAK-1) is a serine/threonine kinase functioning in Toll-like Receptor signaling pathways, and plays an important role in inflammation and immune response. In our studies, we demonstrated that IRAK-1 is involved with the negative regulation of PI3K-Akt dependent signaling pathway induced by insulin and TLR 2&4 agonists. Out data also indicate that IRAK-1 can interact with IRS-1 protein both in vivo and in vitro. The binding sites for the IRAK1-IRS1 biochemical interaction are IRS-1’s PH domain and IRAK-1’s proline-rich LWPPPP motif. Our studies also indicate that IRAK-1 is involved with the negative regulation of glycogen synthesis through inhibiting PI3K-Akt signaling pathway and thus releasing GSK3β’s inhibitory effect on glycogen synthase. Moreover, our studies also suggest that IRAK-1 is involved in the activation of transcription factors CREB and ATF-1 by stimulating CREB-Ser133 and ATF-1 phosphorylation. CREB transcription factor family induces genes involved in cellular metabolism, gene transcription, cell cycle regulation, cell survival, as well as growth factor and cytokine genes. That may partially explain our finding that IRAK-1 may be also involved with cell proliferation and survival pathway.
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