This is a competitive renewal of NIH grant DK33201-19 entitled """"""""Insulin Receptor Substrates and Insulin Action"""""""" which focuses on studying the role of phosphorylation, in particular of the insulin receptor substrates and their partners, in the mechanism of insulin action. Over the past four years we have studied the similarities, differences and potentially complementary roles of various insulin receptor substrates in coupling the insulin receptor tyrosine kinase to down-stream effector systems through the creation and characterization of knockout mice and knockout cell lines; studied the role of the IRS proteins in adipocyte differentiation, glucose transport and control of apoptosis; defined a role for SOCS proteins in insulin resistance; and begun to determine the subcellular compartmentalization and differential partnering of the major IRS family members;. This work has led to the realization that IRS proteins mediate different insulin signaling pathways by providing complementary information, that the exact balance of signaling proteins may affect insulin action both positively and negatively, and that these pathways can be altered in a variety of genetic and nongenetic ways, in insulin resistant states.
The specific aims for the next five years are to: 1) Define the role of specific IRS proteins and their downstream partners in control of gene expression by using Affymetrix oligonucleotide microarrays and cells lacking specific IRS proteins or in which insulin signaling has been blocked by specific pathway inhibitors. 2) Determine the role of the subcellular compartmentalization and trafficking, and the interaction of the IRS proteins and their downstream partners in intact cells using immunofluorescence confocal imaging, 3-dimensional real time imaging, and FRET analysis. 3) Define the role of the SOCS proteins as inhibitors of IRS mediated signaling in acquired and genetically programmed insulin resistance in vivo using anti-sense and by creating insulin resistance in mice heterozygous for deletion of SOCS-1 and SOCS-3. 4) Determine if the genetic modifiers of insulin resistance in the IR/IRS-1 double heterozygous knockout mouse are similar to or different from those in acquired insulin resistance. Identify the chromosomal loci and the specific genes in these loci which modify insulin resistance in the double heterozygous mouse leading to marked differences in diabetic phenotype in C57B1 and 129Sv mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033201-22
Application #
6895473
Study Section
Metabolism Study Section (MET)
Program Officer
Blondel, Olivier
Project Start
1983-12-01
Project End
2008-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
22
Fiscal Year
2005
Total Cost
$666,373
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Rabiee, Atefeh; Krüger, Marcus; Ardenkjær-Larsen, Jacob et al. (2018) Distinct signalling properties of insulin receptor substrate (IRS)-1 and IRS-2 in mediating insulin/IGF-1 action. Cell Signal 47:1-15
Soto, Marion; Herzog, Clémence; Pacheco, Julian A et al. (2018) Gut microbiota modulate neurobehavior through changes in brain insulin sensitivity and metabolism. Mol Psychiatry 23:2287-2301
Altindis, Emrah; Cai, Weikang; Sakaguchi, Masaji et al. (2018) Viral insulin-like peptides activate human insulin and IGF-1 receptor signaling: A paradigm shift for host-microbe interactions. Proc Natl Acad Sci U S A 115:2461-2466
Cai, Weikang; Xue, Chang; Sakaguchi, Masaji et al. (2018) Insulin regulates astrocyte gliotransmission and modulates behavior. J Clin Invest 128:2914-2926
Fujisaka, Shiho; Avila-Pacheco, Julian; Soto, Marion et al. (2018) Diet, Genetics, and the Gut Microbiome Drive Dynamic Changes in Plasma Metabolites. Cell Rep 22:3072-3086
Giles, Daniel A; Moreno-Fernandez, Maria E; Stankiewicz, Traci E et al. (2017) Thermoneutral housing exacerbates nonalcoholic fatty liver disease in mice and allows for sex-independent disease modeling. Nat Med 23:829-838
Kahn, C Ronald; Ussar, Siegfried (2017) Response to Comment on Ussar et al. Regulation of Glucose Uptake and Enteroendocrine Function by the Intestinal Epithelial Insulin Receptor. Diabetes 2017;66:886-896. Diabetes 66:e6
Wang, X; Häring, M-F; Rathjen, T et al. (2017) Insulin resistance in vascular endothelial cells promotes intestinal tumour formation. Oncogene 36:4987-4996
Thomou, Thomas; Mori, Marcelo A; Dreyfuss, Jonathan M et al. (2017) Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542:450-455
Ferris, Heather A; Perry, Rachel J; Moreira, Gabriela V et al. (2017) Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism. Proc Natl Acad Sci U S A 114:1189-1194

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