The overall goal of this program project grant is to elucidate the molecular organization of intracellular signaling pathways involved in mediating the specificity of neural and neuroendocrine responses. The unifying theme is that this organization process depends upon cytoplasmic and nuclear scaffolding proteins that have the ability to integrate diverse signaling cascades. The first goal, addressed primarily by Drs. Goodman and Soderling, is to determine how two widely utilized transcriptional coregulators, CBP and CtBP, contribute to the regulation of genes involved in cell differentiation, development, and apoptosis. While much is known about the interactions of individual transcriptional activators and repressors with specific co-activators or co-repressor , little is known about how these co-regulators are regulated. Experiments in this proposal are designed to increase the understanding of this regulation. The second goal, addressed principally by Drs. Scott, Soderling, and Goodman, is to determine how protein kinase A (PKA) and calcium/calmodulin (CaM)-dependent protein kinases promote changes in cell shape in movement. These studies, which focus on the role of actin polymerization in cellular dynamics, are an extension of the A- kinase anchoring protein (AKAP) hypothesis, a widely accepted model developed in the Scott lab that explains key elements of intracellular signal integration. The regulation of actin polymerization is also addressed in the third goal to characterize the functions of noel mediators of endocytosis and exocytosis. This goal, addressed primarily by Drs. Almers and Scott, utilizes a new technique developed by Dr. Almers, evanescent field microscopy, to visualize components of the endocytotic machinery adjacent to the plasma membrane. Drs. Almers and Goodman will also utilize this approach to elucidate the function of a protein domain that appears to be involved in both transcription and exocytosis. Collaborative experiments involving multiple principle investigators constitute the foundation of the program. Core laboratories for cell culture, protein chemistry, and administration are designed to allow the proposed studies to be performed in an efficient and cost-effective manner.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK044239-12
Application #
6623354
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (J3))
Program Officer
Margolis, Ronald N
Project Start
1992-04-30
Project End
2007-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
12
Fiscal Year
2003
Total Cost
$1,399,759
Indirect Cost
Name
Oregon Health and Science University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Zhang, Qinghong; Wang, Su-Yan; Fleuriel, Capucine et al. (2007) Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex. Proc Natl Acad Sci U S A 104:829-33
Soderling, Scott H; Guire, Eric S; Kaech, Stefanie et al. (2007) A WAVE-1 and WRP signaling complex regulates spine density, synaptic plasticity, and memory. J Neurosci 27:355-65
Felmy, Felix (2007) Modulation of cargo release from dense core granules by size and actin network. Traffic 8:983-97
Zhang, Qinghong; Wang, Su-Yan; Nottke, Amanda C et al. (2006) Redox sensor CtBP mediates hypoxia-induced tumor cell migration. Proc Natl Acad Sci U S A 103:9029-33
Dodge-Kafka, Kimberly L; Langeberg, Lorene; Scott, John D (2006) Compartmentation of cyclic nucleotide signaling in the heart: the role of A-kinase anchoring proteins. Circ Res 98:993-1001
Wan, Lei; Almers, Wolfhard; Chen, Wenbiao (2005) Two ribeye genes in teleosts: the role of Ribeye in ribbon formation and bipolar cell development. J Neurosci 25:941-9
Pawson, Tony; Scott, John D (2005) Protein phosphorylation in signaling--50 years and counting. Trends Biochem Sci 30:286-90
Zhang, Qinghong; Nottke, Amanda; Goodman, Richard H (2005) Homeodomain-interacting protein kinase-2 mediates CtBP phosphorylation and degradation in UV-triggered apoptosis. Proc Natl Acad Sci U S A 102:2802-7
Taraska, Justin W; Almers, Wolfhard (2004) Bilayers merge even when exocytosis is transient. Proc Natl Acad Sci U S A 101:8780-5
Wayman, Gary A; Kaech, Stefanie; Grant, Wilmon F et al. (2004) Regulation of axonal extension and growth cone motility by calmodulin-dependent protein kinase I. J Neurosci 24:3786-94

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