In hypertension, efferent sympathetic activity to post-ganglionic sympathetic nerves and chromaffin cells is increased, contributing to vasoconstriction, sodium retention, and elevations in blood pressure. The chromogranins/secretogranins (chromogranin A [Cga]. Chromogranin B [Cgb]. And secretogranin II [SgII], are a family of acidic proteins found in cores of amine and peptide hormone and neurotransmitter secretory vesicles, such as chromaffin granules and large dense core vesicles of post-ganglionic sympathetic (noradrenergic) axons. Their biologically active fragments act on hormone or neurotransmitter release as well as on target cells at several sites: CgA fragment catestatin inhibits catecholamine release, CgA fragment vasostatin dilates resistance vessels, CgA fragment pancreastatin antagonizes insulin secretion and elevates blood glucose. This proposal develops 3 aims, employing novel targeted photoprotein constructs (luciferase or green fluorescent protein [GFP]) or novel expressed cDNAs, to elucidate how sympathetic outflow changes the composition of catecholamine storage vesicles.
In Aim 1, we employ novel transgenic mouse strains, harboring CgA or SgII promoter/luciferase reporters, to probe mechanisms of stimulus/transcription (stimulus/secretion/synthesis) coupling in the sympathoadrenal system in vivo.
In Aim 2, we use a series of novel, targeted CgA domain/green fluorescent protein (CgA/EGFP) chimeras to discover information within the primary structure of catecholamine storage vesicle proteins that accounts for their trafficking into the regulated secretory pathway.
In Aim 3, we use a novel cDNA expression cloning approach to identify proteins in trans, within the secretory apparatus, which interact with CgA and thereby underlie its trafficking into the regulated secretory pathway. These studies will enhance our understanding of the biosynthesis of catecholamine storage vesicles and the replenishment of their secretory proteins during sympathetic stimulation. Finally, these photoprotein and cDNA reagents can be widely employed by other investigators in elucidating biosynthetic, trafficking, and ion flux events in the sympathochromaffin system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK060702-01A1
Application #
6543868
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Haft, Carol R
Project Start
2002-08-01
Project End
2007-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
1
Fiscal Year
2002
Total Cost
$277,179
Indirect Cost
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
933863508
City
San Diego
State
CA
Country
United States
Zip Code
92161
Zhang, Kuixing; Biswas, Nilima; Gayen, Jiaur R et al. (2014) Chromogranin B: intra- and extra-cellular mechanisms to regulate catecholamine storage and release, in catecholaminergic cells and organisms. J Neurochem 129:48-59
Friese, Ryan S; Altshuler, Angelina E; Zhang, Kuixing et al. (2013) MicroRNA-22 and promoter motif polymorphisms at the Chga locus in genetic hypertension: functional and therapeutic implications for gene expression and the pathogenesis of hypertension. Hum Mol Genet 22:3624-40
Biswas, Nilima; Gayen, Jiaur; Mahata, Manjula et al. (2012) Novel peptide isomer strategy for stable inhibition of catecholamine release: application to hypertension. Hypertension 60:1552-9
Lee, Jason; Aziz, Hossein; Liu, Lin et al. (2011) ?(1)-adrenergic receptor polymorphisms and response to ?-blockade in the African-American study of kidney disease and hypertension (AASK). Am J Hypertens 24:694-700
Friese, Ryan S; Schmid-Schönbein, Geert W; O'Connor, Daniel T (2011) Systematic polymorphism discovery after genome-wide identification of potential susceptibility loci in a hereditary rodent model of human hypertension. Blood Press 20:222-31
Courel, Maïté; Soler-Jover, Alex; Rodriguez-Flores, Juan L et al. (2010) Pro-hormone secretogranin II regulates dense core secretory granule biogenesis in catecholaminergic cells. J Biol Chem 285:10030-43
Bhatnagar, Vibha; Garcia, Erin P; O'Connor, Daniel T et al. (2010) CYP3A4 and CYP3A5 polymorphisms and blood pressure response to amlodipine among African-American men and women with early hypertensive renal disease. Am J Nephrol 31:95-103
Gayen, Jiaur R; Zhang, Kuixing; RamachandraRao, Satish P et al. (2010) Role of reactive oxygen species in hyperadrenergic hypertension: biochemical, physiological, and pharmacological evidence from targeted ablation of the chromogranin a (Chga) gene. Circ Cardiovasc Genet 3:414-25
Zhang, Kuixing; Zhang, Lian; Rao, Fangwen et al. (2010) Human tyrosine hydroxylase natural genetic variation: delineation of functional transcriptional control motifs disrupted in the proximal promoter. Circ Cardiovasc Genet 3:187-98
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

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