This is a competitive renewal of NIH grant DK55545 which is focused on the role of PI 3-kinase in insulin action. PI 3-kinase is important as a critical node in insulin control of metabolism and a key point of divergence of insulin signaling. Using, both in vitro and in vivo approaches, including RNA interference (RNAi) and creation and characterization of mice and cell lines in which specific isoforms of PI 3-kinase have been deleted, i.e. knocked out, at the whole body or tissue specific levels, we have demonstrated multiple, important ways in which this enzyme controls insulin signaling in both positive and negative ways. This includes differences in the activity and properties of the various regulatory subunits of PI 3-kinase, the important role of stoichiometry between regulatory and catalytic subunits in PI 3-kinase signaling and insulin action, and the ability of PI 3-kinase to allow divergence of the downstream signal between Akt and atypical PKCs. In addition, we have demonstrated alterations in PI 3-kinase activity in disease states and the relationship of this pathway to other signaling pathways, including two previously unrecognized connections: one between PI 3-kinase regulatory subunits and activation of the stress kinases JNK and p38, which may link the p85 subunit to serine phosphorylation of IRS proteins in insulin resistant states;and a second between the PI 3-kinase regulatory subunit and the activity of the major PIPS phosphatase PTEN in cells. This has led us to new hypotheses about the important role of PI 3-kinase not only as a site of divergence of the insulin signaling pathways, but also a site of both positive and negative regulation in physiological and pathological states, and a site for cross-talk with other signaling systems, especially the stress kinases. In the next five years, we propose to 1) Dissect the multiple, differential roles of PI 3-kinase regulatory subunits (p85a/b, p50a and p55a/AS53) in insulin signaling, focusing on the potential actions and interactions emanating from the different N-terminal domains of the regulatory subunits that are independent of PI 3- kinase activity;2) Determine the role of the PI 3-kinase catalytic subunits p110a and p11 Ob in divergent insulin signaling in vivo through tissue specific deletion;and 3) Explore new chemical biology approaches to modifying PI 3-kinase mediated signaling in normal and insulin resistant states through the use of small molecule screening and new in vivo gene silencing techniques using nanoparticle delivery systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055545-12
Application #
7808834
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Silva, Corinne M
Project Start
1999-06-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
12
Fiscal Year
2010
Total Cost
$390,071
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Winnay, Jonathon N; Solheim, Marie H; Dirice, Ercument et al. (2016) PI3-kinase mutation linked to insulin and growth factor resistance in vivo. J Clin Invest 126:1401-12
Winnay, Jonathon N; Dirice, Ercument; Liew, Chong Wee et al. (2014) p85? deficiency protects ?-cells from endoplasmic reticulum stress-induced apoptosis. Proc Natl Acad Sci U S A 111:1192-7
Kleinridders, André; Ferris, Heather A; Cai, Weikang et al. (2014) Insulin action in brain regulates systemic metabolism and brain function. Diabetes 63:2232-43
Boucher, Jérémie; Kleinridders, André; Kahn, C Ronald (2014) Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol 6:
Emanuelli, Brice; Vienberg, Sara G; Smyth, Graham et al. (2014) Interplay between FGF21 and insulin action in the liver regulates metabolism. J Clin Invest 124:515-27
Pensa, S; Neoh, K; Resemann, H K et al. (2014) The PI3K regulatory subunits p55? and p50? regulate cell death in vivo. Cell Death Differ 21:1442-50
Pensa, Sara; Lloyd-Lewis, Bethan; Sargeant, Timothy J et al. (2014) Signal transducer and activator of transcription 3 and the phosphatidylinositol 3-kinase regulatory subunits p55? and p50? regulate autophagy in vivo. FEBS J 281:4557-67
Chen, Yin-Ching Iris; Cypess, Aaron M; Chen, Yih-Chieh et al. (2013) Measurement of human brown adipose tissue volume and activity using anatomic MR imaging and functional MR imaging. J Nucl Med 54:1584-7
Chudasama, Kishan Kumar; Winnay, Jonathon; Johansson, Stefan et al. (2013) SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling. Am J Hum Genet 93:150-7
Ræder, Helge; Vesterhus, Mette; El Ouaamari, Abdelfattah et al. (2013) Absence of diabetes and pancreatic exocrine dysfunction in a transgenic model of carboxyl-ester lipase-MODY (maturity-onset diabetes of the young). PLoS One 8:e60229

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