The overall goals of this Merit research proposal have continued to focus on the identification and characterization ofthe insulin signal transduction pathways leading to functional regulation ofthe protein components directly involved in the control of insulin-stimulated glucose uptalce and the maintenance of normai glucose homeostasis. During Vvs period of time, we tiave oor^inued to make excellent progress and the continuing goals and specific aims proposed are direct extension of this ongoing and long temn project tiiat is currentiy in year 28 of continuous funding. In tiiis Merit extension we propose two overall specific aims that will address the crosstalk between the insulin reoeptor and Src family member Fyn tyrosine kinase in mediating energy homeostasis, fatty acid oxidation and insulin sens'lti^flty. We will also examine the interaction of these pathways with the LKB1/AMPK patiiway in mediating glucose uptake and GLUT4 translocation.
In Specific Aim 1, wewiil focus the on mteradion of the Fyn tyrosine kinase to modulsde energy homeostasis and insulin sensitivity by a) Identifying the LKB1 and F^ interactions sites and effects on LKB1 i^osphorylation, assembly and activity state of ti^ LKB1 tiimeiic complex, LKB1/STRAD/M02;b) Identifying the upstream kinases and phosphatases that are responsible for the regulation of Fyn activity in the fasted/refed state;c) Detemiining tSne regulation of tiiese Fyn upstream regulators by fasting, refeeding and insulin under nomial and high fat diet conditions;and d) Detemiining the crystal stmcture for the FynT and FynB isoforms.
In SpecificAim 2, we unlJ examine the insulin, AMPK and Fyn dependent r^uiation of two critical convergent effectors AS160 and AS250 (RGC2) that are thought to modulate distinct aspects of Insulin and exercise-stimulated glucose uptake and GLUT4 translocation by a) Determining the insulin regulation of AS250 (RGC2) and AS160 in vivo;b) Examining the effect of Fyn and AMPK activation of AS250 (RGC2) versus AS160 phosphorylation, Rab8/10 and RalA activation;and c) Analyzing the metabolic phenotype of AS250 (RGC2) conventional and tissue-specific knockout mice.
We had identified a novel signaling crosstalk pathway between the insulin receptor and Src family member Fyn tyrosine kinase in mediating energy homeostasis, fatty add oxidation and insulin sensitivity. Understanding the interactions and mechanisms mediating the regulation of these two pathways will provide us a unique opportunity to utilize new tfierapeutic targets to increase peripheral tissue energy expenditure, reduce tissue and plasma lipids increase weight loss and importantly improve insulin sensitivity.
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