This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The proposed research will determine the role of cytoplasmic polyadenylation element binding protein (CPEB) in mediating mRNA translational control during physiological and pathological neuronal function. The results will have implications for normal neuronal development and developmental dysregulation, as well as pathological processes in aging. CPEB has been recently implicated in models of learning and memory and we have evidence suggesting that CPEB may mediate both neuronal differentiation and neuron apoptosis. The cellular mechanisms underlying CPEB function in brain are largely unknown but appear to be dependent upon NMDA receptor-stimulated activation of Aurora kinase and calcium influx. We will take advantage of the experimentally malleable PCI 2 cell model system and our experience in CPEB-directed regulation of mRNA translation in oocytes to explore these mechanisms. Findings in the PC12 cell system will be tested in cultured hippocampal neurons - a model which more closely mimics conditions found in brain. First, we will define the role and mechanism of CPEB-directed mRNA translational control in the neuro-stimulatory action of nerve growth factor (NGF, PC12 cells ) and N-methyl-D-aspartate (NMDA, hippocampal neurons) and in cell cycle control and apoptosis. We will next characterize the signal transduction pathways that regulate CPEB function. The calcium-dependent CPEB signaling mechanisms may include the cAMP-dependent protein kinase (PKA), the calcium/calmodulin-dependent protein kinase II (CaMKII) or the mitogen-activated protein kinase (MAPK). These studies in PC12 cells and hippocampal neurons will lead to an understanding of the mechanisms of CPEB-mediated mRNA translation. Lastly, we will determine the CPEB isoform distribution in aging and Alzheimer''s Disease (AD) postmortem human brain tissue. Three new isoforms of CPEB have been recently identified in mouse brain which have sequences suggesting they are differentially regulated. The study of these processes in postmortem tissue will allow us to determine their clinical relevance and to identify potential therapeutic avenues in a number of pathological conditions.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
2P20RR020146-06
Application #
7960489
Study Section
Special Emphasis Panel (ZRR1-RI-B (01))
Project Start
2009-08-01
Project End
2010-04-30
Budget Start
2009-08-01
Budget End
2010-04-30
Support Year
6
Fiscal Year
2009
Total Cost
$168,707
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
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Allensworth-James, Melody L; Odle, Angela; Haney, Anessa et al. (2015) Sex Differences in Somatotrope Dependency on Leptin Receptors in Young Mice: Ablation of LEPR Causes Severe Growth Hormone Deficiency and Abdominal Obesity in Males. Endocrinology 156:3253-64
MacNicol, Melanie C; Cragle, Chad E; Arumugam, Karthik et al. (2015) Functional Integration of mRNA Translational Control Programs. Biomolecules 5:1580-99

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