Derangements in the CHGA (chromogranin A) pathway are associated with hypertensive renal disease, a devastating illness found principally in African Americans. During studies of the CHGA gene in African Americans, we have developed evidence for a novel, sequential pathway of events whereby common genetic variation in the 3'-UTR of the mRNA sets off a pathogenic cascade: CHGA 3'-UTR C+87T (rs7610) disrupts a small/non-coding RNA recognition motif (micro-RNA hsa-miR-107), to alter CHGA mRNA translation, eventuating in a decrease in formation of the catestatin (catecholamine release inhibitory) peptide, in association with hypertensive ESRD. Recently we have been able to stabilize synthetic catestatin against degradation, using a Retro-Inverso (R-I) peptidomimetic strategy. Strategy in this proposal, we will explore two points in this sequential pathway - the CHGA 3'-UTR polymorphism and the catestatin peptide - in an attempt to develop pharmacological probes that could eventuate in novel therapeutic approaches. We have already developed compelling preliminary data (proof of principle) for each Aim.
The aims give rise to testable hypotheses that can be confirmed or refuted by the experiments outlined.
Aim -1: CHGA mRNA 3'-UTR micro-RNA motif. We will characterize the human 3'-UTR CHGA polymorphism C+87T (rs7610) and how it disrupts micro-RNA (hsa-miR-107) recognition. We anticipate that this step will elucidate the trigger for decline in catestatin formation, and sugget logical interventions.
Aim -2: CHGA fragment catestatin peptidomimetics. We will characterize stable synthetic variants of a positive (or """"""""rescue"""""""") feature of the cascade: the CHGA peptide catestatin, including its recently synthesized, stable Retro-Inverso (R-I) mimetic. Here we anticipate achieving enhanced activity, stability, and duration of action. Significance these two Aims emerge from a novel pathogenic pathway developed for a disease state of importance to NIDDK. We therefore anticipate that our studies should provide new inroads into therapeutic approaches for a currently intractable health disparity. The proposal thus represents an opportunity to define the genetic basis of a pathogenic pathway, its mechanistic consequences, and its role in risk for development of an important human disease.

Public Health Relevance

The proposal represents an opportunity to define the contribution of the chromogranin/secretogranin system to a major clinical problem: hypertensive kidney disease in minority populations such as African Americans. Our studies probe the mechanism whereby genetic variation may eventuate in the disease, and a novel potential therapeutic inroad into the syndrome;our initial results suggest novel pathophysiological links between genetic variation at an adrenergic gene, and risk for hypertensive nephrosclerosis. The findings should suggest new strategies to approach the mechanism, diagnosis, treatment, and complications of this common yet so far poorly understood disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK094894-03
Application #
8636467
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rasooly, Rebekah S
Project Start
2012-06-15
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
$337,125
Indirect Cost
$119,625
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
Mir, Saiful A; Zhang, Kuixing; Milic, Milos et al. (2016) Analysis and validation of traits associated with a single nucleotide polymorphism Gly364Ser in catestatin using humanized chromogranin A mouse models. J Hypertens 34:68-78
Biswas, Nilima; Maihofer, Adam X; Mir, Saiful Anam et al. (2016) Polymorphisms at the F12 and KLKB1 loci have significant trait association with activation of the renin-angiotensin system. BMC Med Genet 17:21
Zhang, Kuixing; Mir, Saiful A; Hightower, C Makena et al. (2015) Molecular Mechanism for Hypertensive Renal Disease: Differential Regulation of Chromogranin A Expression at 3'-Untranslated Region Polymorphism C+87T by MicroRNA-107. J Am Soc Nephrol 26:1816-25
Rao, Fangwen; Schork, Andrew J; Maihofer, Adam X et al. (2015) Heritability of Biomarkers of Oxidized Lipoproteins: Twin Pair Study. Arterioscler Thromb Vasc Biol 35:1704-11
Mustapic, Maja; Maihofer, Adam X; Mahata, Manjula et al. (2014) The catecholamine biosynthetic enzyme dopamine β-hydroxylase (DBH): first genome-wide search positions trait-determining variants acting additively in the proximal promoter. Hum Mol Genet 23:6375-84
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
Zhang, Kuixing; Deacon, Dekker C; Rao, Fangwen et al. (2014) Human heart rate: heritability of resting and stress values in twin pairs, and influence of genetic variation in the adrenergic pathway at a microribonucleic acid (microrna) motif in the 3'-UTR of cytochrome b561 [corrected]. J Am Coll Cardiol 63:358-68
Zhang, Kuixing; Huentelman, Matthew J; Rao, Fangwen et al. (2014) Genetic implication of a novel thiamine transporter in human hypertension. J Am Coll Cardiol 63:1542-55
Chang, Jamison; Ma, Jennie Z; Zeng, Qing et al. (2013) Loss of GSTM1, a NRF2 target, is associated with accelerated progression of hypertensive kidney disease in the African American Study of Kidney Disease (AASK). Am J Physiol Renal Physiol 304:F348-55
Han, Jia; Liu, Ying; Rao, Fangwen et al. (2013) Common genetic variants of the human uromodulin gene regulate transcription and predict plasma uric acid levels. Kidney Int 83:733-40

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