Stella-Rita Ibeawuchi

Mentor: Curt D. Sigmund, PhD

Year Entered Into Program: 2010

PhD Institution: University of Iowa, 2015

Affiliations

  • Pharmacology

Research Description

Hypertension and type II diabetes are key components of metabolic syndrome which are risk factors in developing cardiovascular disease. If left untreated, hypertension can also lead to other adverse effects such as kidney damage and congestive heart failure. Among the classes of drugs prescribed to treat type II diabetes are the thiazolidinediones (TZDs) which are highly specific agonists of Peroxisome Proliferator-Activated Receptor gamma (PPARγ), a nuclear receptor and ligand activated transcription factor. The beneficial effects of TZDs include lowering blood pressure and this occur independent of improved glycemic control. The importance of PPARγ in blood pressure regulation is highlighted by clinical reports that human subjects with dominant negative mutations exhibit severe early onset hypertension in addition to insulin resistance, and type II diabetes. However, the mechanisms by which PPARg regulates blood pressure remains largely unknown. A common feature of hypertension is increased activity of the monomeric G protein RhoA. Previous studies suggest that the activation of PPARγ regulates vascular tone and blood pressure by inhibiting the RhoA/Rho kinase signaling. Sigmund lab has generated a transgenic mouse model expressing the P467L dominant negative (DN) mutant of PPARγ specifically in vascular smooth muscle (SP467L mice). We have identified potential novel PPARγ target genes using gene expression profile and we hypothesize that these genes may mediate contractile state of vessels in response to PPARg activation and interference. My research it to examine the importance of the Rho Kinase (ROCK) signaling pathways in smooth muscle cells (SMC) of SP467L mice specifically evaluating the roles of the proposed novel PPARγ target genes Rhobtb1 (atypical Rho GTPase) and DOCK11 (a Rho-GTP exchange factor), that might be involved with alterations in the RhoA-ROCK signaling pathway. These studies have the potential to advance our understanding of how PPARγ regulates vasomotor tone and blood pressure. The significance of this study being that as PPARγ regulates arterial pressure; the novel target genes identified may provide new pharmacological targets that will promote the benefits of PPARγ while minimizing the negative effects associated with TZDs.

Abstracts

  • American Heart Association (AHA) Predoctoral Fellowship, 2014-2015
  • Pharmaceutical Reseaerch and Manufacturers of America Foundation (PhRMA), 2015, due to overlap it was turned back

Publications

  1. Ibeawuchi, S., Dasgupta, S., Meng, C. and Ding, C.: Source localization using a maximum likelihood/semidefinite programming hybrid.3rd ICST. 585-588, 2008.
  2. Dasgupta, S., Ibeawuchi, S-R.C. and Ding, Z.: Optimum sensor placement for source monitoring under log - normal shadowing in three dimensions.9th ISCIT. 376-381, 2009.
  3. Dasgupta, S., Ibeawuchi, S.C. and Ding, Zhi: Optimum sensor placement for localization under log-normal shadowing.2010 ISCIT. 204-208, 2010.
  4. Yang, J., Huang, J., Maity, B., Gao, Z., Lorca, R.A., Gudmundsson, H., Li, J., Stewart, A.,Swaminathan, P.D., Ibeawuchi, S-R.,Shepherd, A., Chen, C.K., Kutschke, W., Mohler, P.J., Mohapatra, D.P., Anderson, M.E. and Fisher, R.A.:RGS6, a modulator of parasympathetic activation in heart.Circ Res. 107(11):1345-1349, 2010.PMCID: PMC2997524
  5. Pelham, C.J., Ketsawatsomkron, P., Groh, S., Grobe, J.L., de Lange, W.J., Ibeawuchi,S.R., Keen, H.L., Weatherford, E.T., Faraci, F.M., Sigmund, C.D.: Cullin-3 Regulates Vascular Smooth Muscle Function and Arterial Blood Pressure via PPARγ and RhoA/Rho-Kinase. Cell Metab. 16(4):462-72, 2012. PMCID: PMC3474846  
  6. Ibeawuchi SR, Agbor LN, Quelle FW, Sigmund CD.: Hypertension-causing Mutations in Cullin3 Protein Impair RhoA Protein Ubiquitination and Augment the Association with Substrate Adaptors. J Biol Chem 290(31):19208-17, 2015.  PMCID: PMC4521042
  7. Agbor LN, Ibeawuchi SC, Hu C, Wu J, Davis DR, Keen HL, Quelle FW, Sigmund CD.: Cullin-3 mutation causes arterial stiffness and hypertension through a vascular smooth muscle mechanism. JCI Insight 1(19)e91015, 2016.  PMCID: PMC5111503

Research