Chromogranin A (CGA) is co-stored with catecholamines in chromaffin granules and co-released in response to sympathoadrenal stimulation. From CGA pro-protein several biologically active peptides including catecholamine release-inhibitory peptide catestatin are derived. Nicotine, the primary component of tobacco, stimulates secretion of catecholamines, augments biosynthesis of CGA, and, as a nicotinic cholinergic agonist, promotes desensitization of catecholamine secretion. In developed countries, tobacco use is the largest single cause of premature death and heart disease the most common cause of death. Studies have demonstrated that smoking, diabetes and hypertension are major risk factors for coronary heart disease. Catestatin level is diminished in hypertensive patients. Chga knockout (Ko) mice have been generated in this laboratory. Their striking phenotypic characteristics include elevated systolic blood pressure (SBP), decreased catecholamines levels, loss of chromaffin granules and partial prenatal lethality. The proposed study specifically aims to: 1. Rescue the Chga-Ko phenotype by introducing the human CHGA gene using bacterial artificial chromosome (BAC) transgenic approach. 2. Sequencing of the human CHGA gene, revealed three non-synonymous SNPs (single nucleotide polymorphism) in the catestatin sequence. The proposed study will analyze the differences in regulation of SBP, catecholamine levels and nicotine cholinergic responses between the wild type and mutant variants of CGA. Variant catestatin peptides will be synthesized and administered into Chga -/- mice. The 3 mutant CHGA-BAC mouse models (Gly364Ser, Pro370Leu, and Arg374GIn) will also be generated to explore the significance of such polymorphisms. 3. Finally, the CGA variants will be assessed for processing by proteases in vitro and in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK069613-04
Application #
7342909
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2005-03-15
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
4
Fiscal Year
2008
Total Cost
$107,747
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Dev, Nagendu B; Mir, Saiful A; Gayen, Jiaur R et al. (2014) Cardiac electrical activity in a genomically ""humanized"" chromogranin a monogenic mouse model with hyperadrenergic hypertension. J Cardiovasc Transl Res 7:483-493
Vaingankar, Sucheta M; Li, Ying; Biswas, Nilima et al. (2010) Effects of chromogranin A deficiency and excess in vivo: biphasic blood pressure and catecholamine responses. J Hypertens 28:817-25
Vaingankar, Sucheta M; Li, Ying; Corti, Angelo et al. (2010) Long human CHGA flanking chromosome 14 sequence required for optimal BAC transgenic ""rescue"" of disease phenotypes in the mouse Chga knockout. Physiol Genomics 41:91-101
Biswas, Nilima; Rodriguez-Flores, Juan L; Courel, Maite et al. (2009) Cathepsin L colocalizes with chromogranin a in chromaffin vesicles to generate active peptides. Endocrinology 150:3547-57