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269 Development of Novel Protein Expression Technologies for Glycosylated Cancer Related Proteins

Number of anticipated awards: 4
(Fast-Track proposals will be accepted.)
Budget (total costs): Phase I: $150,000;
Phase II: $750,000

The deadline for receipt of all contract proposals submitted in response to this solicitation is:
5:00 p.m. Eastern Standard Time
Monday, November 3, 2008

Summary:
The purpose of this initiative is to provide support for the development of novel technologies for the expression of cancer-related glycosylated proteins. Many proteins become post-translationally modified (PTM) during the “secretory process” which involves of a journey from their site of synthesis in the rough endoplasmic reticulum (ER), through the Golgi apparatus and then to various cellular and extracellular destinations. Various covalent modifications often occur, either during or after assembly of the polypeptide chain, that are indispensable for the activity of these proteins. Knowledge of these modifications is extremely important because they may alter the proteins’ physical and chemical properties, folding, conformation distribution, stability, activity, and consequently, function. Moreover, the modification itself can act as an added functional group. Examples of the biological effects of protein modifications include glycosylation, phosphorylation, acetylation, and amidation. Of these, the most complex procedure, involving several enzymes, is glycosylation. Hence, glycoproteins are the most diverse group of biological compounds that are ubiquitous constituents of almost all living organisms. A given glycoprotein may contain N-linked (asparagine-linked) oligosaccharide chains only, O-linked (threonine- or serine-linked) oligosaccharide chains only, or both. The carbohydrate units of glycoproteins exhibit considerable variation in size and structure ranging from mono- or disaccharide- to a branched oligosaccharide composed of as many as 20 monosaccharide residues. Consequently, the analysis of proteins and their post-translational modifications is particularly important for the study of cancer, neurodegenerative diseases, heart disease and diabetes.

Specifically, the NCI is interested in proposals that focus on the development of glycosylated human proteins. Proposals should explicitly describe how the proposed technology/system will develop/express, isolate and characterize the glycosylated proteins.

Project Goals:
Increasing demand for recombinant glycosylated proteins has focused research on techniques for improving protein expression and controlling post-translational processing. The purpose of this project is to stimulate the development on all aspects of glycosylated protein expression including novel cell systems, expression vectors, and culture conditions. Glycosylated proteins selected for production are to entail low abundance cancer-related proteins from bodily fluids preferably developed in coordination with the Clinical Proteomics community. Furthermore, these glycosylated proteins must be made available as a resource to the greater scientific community.

Offerors are encouraged to coordinate selection of analytes with the Clinical Proteomics Technologies for Cancer community during Phase I. Targets for Phase II are to be selected in coordination with this community from glycosylated biomarker candidates listed in the following reference: Malu Polanski and N. Leigh Anderson. (2006) “A List of Candidate Cancer Biomarkers for Targeted Proteomics.” Biomarker Insights 2:1-48.

Phase I Activities and Expected Deliverables

• Demonstration of feasibility of the innovative glycosylated protein development approach.
• Produce an initial glycosylated protein production prototype.
• Produce evidence that the glycosylated proteins are well characterized (preferably using MS-based techniques).
• Demonstrate that glycosylated proteins can be made reproducibly and economically.
• Generate at least 10 glycosylated targets (offerors are encouraged to select targets in coordination with the Clinical Proteomic Technologies for Cancer community).
• Research should be proposed with quantitative feasibility milestones.

Phase II Activities and Expected Deliverables

• Generate at least 100 glycosylated targets (to be selected in coordination with the Clinical Proteomic Technologies for Cancer community)
• Glycosylated proteins are to be well characterized (preferably using MS-based techniques).
• Work with the Clinical Proteomic Technologies for Cancer community to integrate glycosylated proteins into the technology assessment programs and greater scientific community.
• Research should be proposed with quantitative feasibility milestones.