Grants and Contracts Details
Description
Insulin is beneficial for cardiac cell survival and function. For example, impaired insulin action contributes to
pathological conditions such as diabetic cardiomyopathy. Conversely, increased insulin signaling is thought to
protect cardiomyocytes from ischemic injury when administered as part of Glucose-Insulin-Potassium (GIK)
infusion therapy. Although insulin plays a fundamental role in cardioprotection and cardiac maintenance, the
mechanism by which insulin promotes these effects is not well understood. Insulin binding to its receptor
promotes the activation of the insulin receptor substrate (IRS) via insulin receptor-mediated phosphorylation of
tyrosine residues on IRS. Activation of IRS mediates activation of intracellular signaling cascades, in part, by
activating the small GTPase, Ras. Ras interacts with multiple effectors to stimulate both cardioprotective (e.g.
PI3-kinase-Akt and Raf-MEK-ERK) and apoptotic (e.g. MEKK1-JNK) cascades. Identifying the factors that
modulate these kinase cascades is therefore, of fundamental importance to understanding cardiac
pathophysiology. We have identified the RaIGEF-like factor (Rlf) as a protein that interacts with Ras in the
heart. My preliminary results obtained in neonatal rat ventricular myocytes (NRVMs) indicate that Rlf
overexpresion enhances insulin-induced IRS phosphorylation and PI3-kinase-Akt activation while inhibiting
insulin-induced JNK activation. Whether IRS is specifically involved in Rlf-mediated upregulation of Pl3-kinase
activation and the role of Rlf-mediated Ral activation is not known and will be investigated in this proposal. My
hypothesis is that Rlf enhances insulin-induced Pl3-kinase activation through Ral mediated inhibition of JNK
and enhanced IRS activation. The aims for this proposal are: Specific Aim 1: To determine the role of JNK and
IRS in Rlf-mediated upregulation of insulin-induced Pl3-kinase activation and; Specific Aim 2: To determine the
role of Ral in JNK inhibition and enhancement of IRS and Pl3-kinase activation.
Status | Finished |
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Effective start/end date | 7/1/06 → 6/30/08 |
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