Dianne Perez Laboratory

Dianne Perez, PhD

Staff
Email: [email protected]
Location: Cleveland Clinic Main Campus

Research

Our body′s “fight or flight” response is regulated through a chemical called adrenaline released through nerve endings. Adrenaline works by attaching to proteins called receptors that are placed in essentially every organ and tissue throughout the body. How one drug can regulate all the organs in the body at the same time and do so in variant ways is through different adrenergic receptors called subtypes. I work on different adrenergic receptor subtypes and can demonstrate how one subtype can protect the heart against damage from heart attacks or can increase your ability to remember things by growing new neurons in the brain. 

Alpha1-adrenergic receptors (ARs) are G-Protein Coupled Receptors (GPCRs) that bind Norepinephrine (NE) and regulate neurotransmission through alpha1-AR subtypes (alpha1A, alpha1B, alpha1D) that are known to play roles in learning, memory, synaptic function and long term potentiation (LTP). Previous studies assessing their roles in cognition have been inconsistent because of the use of non-selective ligands and many of these studies were published pre-2000 before the characterization of the cloned receptor subtypes and the subsequent development of animal models. Drug development has mostly stopped for this receptor since activation of alpha1-ARs increase blood pressure (BP). We now know through transgenic animal models we developed that the different alpha1-AR subtypes can regulate opposing phenotypes in the brain. These studies were possible because my laboratory developed unique mouse models that systemically over express constitutively active mutations (CAMs) in alpha1-ARs that are chronically activated even when an agonist is not present. These mice provide selectivity in alpha1-AR subtype signaling when selective commercial ligands were unavailable.

Using these and KO mice, we discovered that chronic stimulation of the alpha1B-AR subtype is apoptotic and neurodegenerative while chronic stimulation of the alpha1A-AR subtype is neuroprotective and cognitive-enhancing. Using EGFP-tagged receptors in the alpha1A-AR transgenic mice and confirmed with beta-galactosidase antibodies in the alpha1A-AR KO, we found that the alpha1A-AR subtype is highly expressed in the cognitive centers of the brain. As CAM alpha1A-AR mice have increased hippocampal synaptic plasticity and enhanced LTP, increased lifespan, and hippocampal neurogenesis, there is justification that agents that stimulate alpha1A-AR activity may be beneficial to AD. Normal mice treated with the mildly selective alpha1A-AR partial agonist cirazoline, increased both neurogenesis and cognition while alpha1A-AR KO mice had cognitive decline. 

We have developed a novel small molecular weight compound that is bioavailable and is a positive allosteric molecule (PAM) of the alpha1A-AR. Compound 3 (cmpd-3) is selective for the alpha1A-AR with nM affinity at its low binding affinity site and does not bind to the other two alpha1-AR subtypes. Cmpd-3 is also conformationally-selective and only affects the NE-bound receptor and does not affect the epinephrine (EPI)-bound receptor. Cmpd-3 is not an ago-agonist and does not invoke signaling on its own. Moreover, cmpd-3 is also signaling-biased and potentiates the NE-mediated cAMP response and p-CREB which is responsible for the cognitive benefits of NE in the brain with no effects on the NE-mediated inositol phosphate (IP) response. The IP response releases calcium and causes increased BP through vasoconstriction, suggesting that cmpd-3 would not invoke a BP response, which we confirmed in vivo with high-dosage and long-term treatment studies. We have shown in two different Alzheimer's Disease mouse models that cmpd-3 can restore LTP and amyloid biomarker profile to non-disease levels with increased cognitive behavior.

Biography

My early publications were seminal in the alpha1-adrenergic receptor (alpha1-AR) field, starting with cloning the receptors, determining the correct nomenclature based upon pharmacology, and initially characterizing their signal transduction pathways. After the initial characterization of the alpha1-ARs, I next mapped out the ligand-binding pocket for both agonists, antagonists, and specialized ligands called imidazolines. This collection of work was very useful to the pharmaceutical industry during the 1990s and 2000s, as several drugs were synthesized based upon my structure-function studies to treat conditions such as stress urinary incontinence and benign prostatic hyperplasia. My studies were also seminal for providing insight into how these receptors are activated, by showing the specific amino acid residues involved in the activation process, and the discovery of constitutivel activity. Several of these amino acid residues have been shown subsequently to be involved in similar mechanisms in other G-protein-coupled receptors. After the structure-function studies, we created unique transgenic mouse models using large fragments of the isogenic promoters to over express wild type and constitutively active alpha1-AR subtypes in all natively expressing tissues. These mouse models are state of the art in the ability to express and characterize subtype-selective signaling and revealed novel physiology and pathophysiology never before associated with these receptors. I have now expanded my studies into drug discovery and the design and characterization of allosteric alpha1A-AR compounds that can activate the receptor and can disease-modify Alzheimer's Disease.

AWARDS

1978, The Baush and Lomb Science Award; 1980, The Lubrizol Scholarship; 1980, The John W. Chittum Price in Organic Chemistry; 1981, The Cary R. Wagner Prize in Chemistry; 1982, The William Z. Bennett Prize in Chemistry; 1982, Phi Beta Kappa; 1991, NIH National Research Service Award (Individual); 1992, William E. Lower Basic Science Award (CCF); 1992, Finalist, Young Investigator Award (CCF); 1994-1999, National American Heart Association Peer Review; 1996-2007, Established Investigator of the AHA; 1997-2002, Mid-American Research Consortium Peer Review of the American Heart Association; 1998-, Editorial Board, Mol. Pharmacology; 2004-2011-Associate Editor, Mol. Pharmacology; 1998-2006, Editorial Board, JPET; 2000-, Editorial Board, Receptors and Signal Transduction; 2004-2007President, Mol. Pharmacology Division of ASPET; 2005-2008Chair,Ohio Valley & Great Rivers Affiliate, AHA research committee & Board of Directors; 2005-2007 Editorial Board,Am J Phys- Cell Physiology; 2005-08, OVA-AHA Board of Directors; 2010-current, Associate Editor-Pharmacological Reviews; 2017-Harrington-ADDF Scholar Award; 2019-20 LRI Accelerator Award, Cleveland Clinic; 2020  Outstanding Innovation Award in Therapeutics and Diagnostics (Cleveland Clinic Innovations)

Education & Professional Highlights

2004-  Full Staff and Professor, Dept. Cardiovascular & Metabolic Sciences, Cleveland Clinic Foundation

2001-2004   Associate Staff, Department of Molecular Cardiology, The Cleveland Clinic Foundation

1996–2000  Assistant Staff, Department of Molecular Cardiology, The Cleveland Clinic Foundation

1993–1995   Project Scientist, Department of Cardiovascular Biology, The Cleveland Clinic Foundation

1992–1993   Research Associate, Department of Cardiovascular Biology, The Cleveland Clinic Foundation

1989–1991   Fellow, Department of Heart and Hypertension Research, The Cleveland Clinic Foundation

1988–1989   Fellow, Department of Eye Research, Doheny Eye Institute, Los Angeles, California

1988  Ph.D., Chemistry, California Institute of Technology

1982   B.A., Chemistry and Biology, (with Honors) The College of Wooster