One-fifth of the genome codes for secretory proteins;a small subset of these proteins represent peptide hormone signaling molecules. This proposal addresses the identification of novel secretory molecules involved in the control of metabolic function. Since the majority of neuroendocrine signaling molecules undergo proprotein convertase-mediated maturation, we plan to exploit the presence of genuinely cleavable sites in novel precursors to validate a set of potential peptide precursors. We will then test the bioactivity of correctly modified peptide products derived from these proteins. These assays will identify biologically active peptides acting on tissues that are key effectors of metabolic control: fat, liver and muscle. The proposed project represents a collaboration of the Lindberg laboratory with the secretory protein company Five Prime Therapeutics. Briefly, bioinformatics identification of large numbers of putative precursors by Five Prime will be followed by screening of HEK-expressed proteins with purified recombinant convertases (Lindberg laboratory). The information generated by the processing screen will then be used to direct large-scale recombinant protein production of promising precursors in the Lindberg laboratory. These purified precursors will be subjected to in vitro proteolytic and terminal maturation reactions in the Lindberg laboratory, and the resulting peptide products will then be tested in six metabolic assays targeted at fat, liver and muscle cell glucose metabolism at FivePrime Therapeutics. We expect that these studies will result in the identification of several novel peptide hormones contributing to metabolic control. These results should aid in our complete understanding of the hormonal control of glucose and lipid metabolism.

Public Health Relevance

This is a discovery project which focuses on the identification of novel bioinformatics-identified peptide hormones. We will employ chemical processing of candidate precursors using physiological enzymes to make peptide mixtures which we will test in six different assays of glucose and lipid metabolism. We expect that these studies will result in the identification of several novel peptide hormones contributing to metabolic control.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK084481-02
Application #
7849751
Study Section
Special Emphasis Panel (ZRG1-EMNR-H (02))
Program Officer
Malozowski, Saul N
Project Start
2009-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$187,500
Indirect Cost
Name
University of Maryland Baltimore
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Ozawa, Akihiko; Lick, Adam N; Lindberg, Iris (2011) Processing of proaugurin is required to suppress proliferation of tumor cell lines. Mol Endocrinol 25:776-84