Dr. Perez

Dianne M. Perez, Ph.D.

Staff

Department of Molecular Cardiology
Lerner Research Institute / NB50
9500 Euclid Avenue
Cleveland, Ohio 44195
Telephone: (216) 444-2058
Fax: (216) 444-9263
perezd@ccf.org
 

Area of General Research Interest:

Physiological studies of adrenergic receptors

Current Program:

  • Differential signaling of alpha1-adrenergic subtypes
  • Physiology of alpha1-adrenergic receptor subtypes
  • Alpha1-adrenergic receptors in neurogenesis and cognition

Investigators:

  • Papay, Robert, B.S., Lead Technologist

Collaborators:

  • Van A. Doze, PhD, Associate Professor, Department of Pharmacology, Physiology, & Therapeutics, The University of North Dakota, ND
  • Michael T. Piascik, PhD, Professor, Department of Pharmacology and the Vascular Biology Research Group, University of Kentucky College of Medicine, Lexington, KY

Brief Description:

Alpha1-adrenergic receptors (ARs) are members of the superfamily of G-protein-coupled receptors (GPCRs) that regulate the sympathetic nervous system. The three alpha1-AR subtypes (alpha1A, alpha1B, alpha1C) regulate growth and smooth muscle contraction and particularly become important in cardiovascular function during disease states. Drugs that bind alpha1-adrenergic receptors are a current treatment for high blood pressure, arrhythmias, and current research suggests that the alpha1A-AR subtype is cardioprotective against ischemia and heart failure. However, the mechanism by which drugs bind and influence receptor function, particularly between the subtypes, is not clear.

My laboratory is interested in three major areas of research: 1) Differential signaling of the alpha1-AR subtypes and their pertinence to cardiovascular and neurological functions; 2) The role of the individual alpha1-AR subtypes in physiology and disease; and 3) How alpha1-ARs regulate neurogenesis and cognitive functions.

In the first area of study, we used DNA microarrays and proteomics to explore potential differences in the function of the three alpha1-AR subtypes. We have found some subtype-specific changes in gene-expression and signal transduction and will explore these differences in physiological settings using transgenic and knock-out mice of the alpha1-AR subtypes.

The second area of research is the role of alpha1-adrenergic receptors in physiology and disease. We have recently found that systemic over expression of the alpha1B-AR subtype is maladaptive for both the heart and the brain, while chronic alpha1A-AR stimulation is protective in the same tissues. In the brain, chronic alpha1B-AR stimulation induces symptoms and a movement disorder similar to a neurodegenerative disease called Multiple System Atrophy (MSA). This is the first reported animal model for MSA. We are continuing to characterize our model and to determine the mechanism. Antagonists to the alpha1-AR reverse symptoms in these mice, and recently was used to essentially erase all symptoms for a patient with a MSA diagnosis. Our work may eventual translate to humans and provide the first therapy for this debilitating disease. In the heart, the alpha1B-AR induces cardiac dysfunction and inflammation. Interestingly, the alpha1A-AR subtype in the transgenic mouse model can protect the heart from ischemic damage and apoptosis.

In the brain, the alpha1A-AR protects against epilepsy, induces neurogenesis and increases cognition. Our third area of research is to probe further into this mechanism of neuroprotection and enhanced cognition. These alpha1A-AR mice are really smart! If you give an alpha1A-AR agonist to normal mice, you can increase learning and memory by 2-fold.

Transgenic mice with GFP tags are localizing the protein expression of these receptors in the brain and other tissues. Since GPCR antibodies are notoriously weak for endogenous detection, these animal models are useful for tracking these receptors in vivo.

Key References:

  • Gupta MK, Papay RS, Jurgens, CWD, Gaivin RJ, Shi T, Doze VA, Perez DM. Alpha1-adrenergic receptors regulate neurogenesis and gliogenesis. Molecular Pharmacology, 76(2):314-325, 2009. PMID: 19487244
  • Perez DM, Papay RS, & Shi T. Alpha1-adrenergic receptor stimulates IL-6 expression and secretion through both mRNA stability and transcriptional regulatoin: involvement of p38 MAPK and NF-kappB. PMID:19363165
  • Naga Prasad SV, Duan ZH, Gupta MK, Surampudi VS, Volinia S, Calin GA, Kotwal A, Moravec CS, Starling RC, Perez DM, Sen S, Wu Q, Plow EF, Croce CM, Karnik S. Unique microRNA profile in end-stage heart failure indicates alterations in specific cardiovascular signaling networks. J Biol Chem, 284(40):27487-27499, 2009. PMID: 19641226
  • Gominak S, Plotkin GM, DM Perez. Curative treatment of multiple system atrophy with the alpha1-adrenergic receptor antagonist, terazosin: A case report. [submitted]
  • Jane-wit D, Altuntas CZ, Johnson JM, Yong S, Wickley PJ, Clark P, Wang Q, Popovic ZB, Penn MS, Damron DS, Perez DM, Tuohy VK. Beta1-adrenergic receptor autoantibodies mediate dilated cardiomyopathy by agonistically inducing cardiomyocyte apoptosis. Circulation 116:399–410, 2007. Epub 2007 July 9. PMID: 17620508
  • Shi T, Duan ZH, Papay R, Pluskota E, Gaivin RJ, de la Motte CA, Plow EF, Perez DM. Novel alpha1-adrenergic receptor signaling pathways: secreted factors and interactions with the extracellular matrix. Mol Pharmacol 70:129–142, 2006. PMID: 16617165       
  • Papay R, Gaivin R, Jha A, McCune DF, McGrath JC, Rodrigo MC, Simpson PC, Doze VA, Perez DM. Localization of the mouse alpha1A-adrenergic receptor (AR) in the brain: alpha1A-AR is expressed in neurons, GABAergic interneurons and NG2 oligodendrocyte progenitors. J Comp Neurol 497:209–222, 2006. PMID: 16705673
  • Rorabaugh BR, Gaivin RJ, Papay RS, Shi T, Simpson PC, Perez DM. Both alpha(1A) and alpha(1B)-adrenergic receptors crosstalk to down regulate beta(1)ARs in mouse heart: coupling to differential PTX-sensitive pathways. J Mol  Cell  Cardiol 39:777–784, 2005. Epub 2005 September 19. PMID: 16171811
  • Rorabaugh BR, Ross SA, Gaivin RJ, Papay RS, McCune DF, Simpson PC, Perez DM. alpha1A- but not the alpha1B-adrenergic receptor precondition the ischemic heart by a staurosporine-sensitive, chelerythrine-insensitive mechanism. Cardiovasc Res 65:436–445 2005. PMID: 15639483
  • Papay R, Gaivin R, McCune DF, Rorabaugh BR, Macklin WB, McGrath JC, Perez DM. Mouse alpha1B-adrenergic receptor is expressed in neurons and NG2 oligodendrocytes. J Comp Neurol 478:1–10, 2004. PMID: 15334645
  • Ross SA, Rorabaugh BR, Chalothorn D, Yun J, Gonzalez-Cabrera PJ, McCune DF, Piascik MT, Perez DM. The alpha(1B)-adrenergic receptor decreases the inotropic response in the mouse Langendorff heart model Cardiovasc Res 60:598–607, 2003. PMID: 14659805
  • Gonzalez-Cabrera PJ, Gaivin RJ, Yun J, Ross SA, Papay RS, McCune DF, Rorabaugh BR, microarrays: coupling to interleukin-6 secretion but differences in STAT 3 phosphorylation and gp-130. Mol. Pharmacol 63:1104–1116, 2003. PMID: 12695539
  • Yun J, Gaivin RJ, McCune DF, Boongird A, Papay RS, Ying Z, Gonzalez-Cabrera PJ, Najm I, Perez DM. Gene expression profile of neurodegeneration induced by alpha1B-adrenergic receptor overactivity: NMDA/GABAA dysregulation and apoptosis. Brain 126:2667–2681, 2003. PMID: 12937073
  • Yun J, Zuscik MJ, Gonzalez-Cabrera P, Ross SA, McCune DF, Ross SA, Gaivin R, Piascik MT, Perez DM. Gene expression profiling of alpha(1b)-adrenergic receptor-induced cardiac hypertrophy by oligonucleotide arrays. Cardiovasc Res 57:443–455, 2003. PMID: 12566117