Area:
translational control
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High-probability grants
According to our matching algorithm, Nahum Sonenberg is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2002 — 2005 |
Sonenberg, Nahum |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Regulation of Mrna 5'-3'Interactions: the Role of Paips
DESCRIPTION (provided by applicant): The long-term objective of our research is to understand the biological function of a family of transaltional modulators known as PABP interacting protiens (Paips) which were first cloned in our laboratory. These proteins mediate their effects on translation by interacting with the poly(A) binding protein (PABP). Previous work has shown that Paipi stimulates translation, whereas Paip2A and Paip2B inhibit translation. The specific aims of this proposal are to further our understanding of the molecular mechanism of Paip action, to discover how Paip function is regulated, and to elucidate the biological significance of this family of proteins. A variety of in vitro and in vivo experiments will be carried out to study the Paip1PABP interactions, to dissect their mechanism of action, and to identify novel Paip interacting proteins. Paip expression and function will be inhibited by the RNA interference technique and the use of small cell-permeable peptides. Paip phosphorylation will be explored to elucidate the signaling pathways impinging upon Paip function. To this end, phosphopeptide mapping and 2-dimensional isoelectric focusing and SDS-PAGE will be used to study the phosphorylation states of the Paips under various environmental conditions and upon treatment with pharmacological kinase inhibitors. The phosphoresidues in the proteins will be identified and mutated. Resulting proteins will be assayed using in vitro and in vivo translation experiments to discover their functional importance. Elucidation of the physiological role of the Paips will be pursued by Paip overexpression and knockout (KO) experiments in Drosophila. Paip null flies will be generated by P-element insertion or homologous recombination. The generation of KO mice devoid of the individual Paip genes will also be pursued by homologous recombination. In the case of Paip2A and Paip2B, which are functional homologs, a Paip2AIPaip2B KO mouse will be generated. KO mice will be analyzed for phenotypic abnormalities.
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1 |
2008 — 2011 |
Sonenberg, Nahum |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Translational Control by Poly(a)-Binding Protein and Its Modulators (Paips)
[unreadable] DESCRIPTION (provided by applicant): The long-term objective of our research is to understand the mechanism of translation initiation in eukaryotes, its control under physiological conditions, and deregulation in diseases, such as cancer, diabetes and virus infection. Here, we propose to pursue our studies on the mechanism of function of the mRNA poly(A) binding protein (PABP) in translation initiation, and its regulation by members of a family of proteins known as PABP- interacting proteins (Paips), which were discovered in our laboratory. We demonstrated that Paip1 stimulates translation, whereas Paip2A and Paip2B inhibit translation. We propose three specific aims, which are as follows: 1. Investigate the function of a newly discovered complex, eIF3-Paip1. The molecular mechanism by which Paip1 stimulates translation will be studied, including a detailed structural characterization of the Paip1- eIF3 interaction. 2. Characterize the signaling pathways that regulate eIF3-Paip1 complex formation. We will determine whether phosphorylation of eIF3 regulates Paip1 binding and activity. Mutational analyses will be performed to study downstream effects of eIF3 phosphorylation on Paip1 function in translation. 3. Elucidate the physiological roles of Paip2A and Paip2B in animal models. Single knockout (KO) of Paip2A and Paip2B mice have recently been generated in our lab. Based on the known tissue distribution of the Paip2 proteins, we also intend to generate brain- and pancreas-specific KO mice. Mice will be subjected to complete phenotypic, pathological and histological examinations, and will be studied for effects on beta-cell regulation in the pancreas and on synaptic plasticity and memory formation in the brain. PUBLIC HEALTH RELEVANCE Many major diseases including cancer, diabetes and obesity arise because of defects in the control of the synthesis of proteins. We are studying an important example of such control, which involves a protein called poly(A) binding protein and its binding partners. Poly(A) binding protein binds to the tail of the genetic material (messenger RNA) that serves as template for the synthesis of all proteins in the cell. [unreadable] [unreadable] [unreadable]
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