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CHOTANI LABORATORY Project #1: Mechanisms of expression and mobilization of micro-vascular smooth muscle α2C-adrenoceptors (α2C-ARs) The key objective of this project is to understand the biology of the G protein coupled α2- adrenoceptor subtype C (α2C). This receptor has been implicated in the cold-triggered spasms in blood vessels of individuals suffering from Raynaud’s phenomenon, secondary Raynaud’s associated with scleroderma, and hand-arm vibration syndrome. A unique feature of α2C-AR regulation includes intracellular retention. The receptor translocates to the plasma membrane under select physiological conditions of vascular stress, engaging with the agonist norephinephrine, and eliciting a biological response of vasoconstriction. Our recent work has uncovered an essential role of the cytoskeleton in receptor mobilization to the cell surface. We are developing a peptide decoy that may reduce cell surface receptor mobilization, and may have therapeutic potential.
Project #2: The second messenger cyclic AMP- and cooling-coupled signature molecules in micro-vascular smooth muscle cells This project includes examination of signature microRNAs and proteins in human vascular smooth muscle cells utilizing chip/PCR analyses and 2D-proteomics (fluorescence difference gel electrophoresis), respectively. This approach will potentially lead to identification of physiologically relevant "vasculo-protective" players (or markers), conferring "stress-tolerance" to cells during cooling or vascular injury. Preliminary studies have identified specific proteins and microRNAs altered by cyclic AMP and by cooling.
Project #3: Role of the Ras-related small GTPase Rap1A in the cardiovasculature Rap1 acts as a molecular switch, coupling extracellular stimulation to intracellular signaling through the second messenger cyclic AMP. The key objective of this project is to examine the role of this protein in cell attachment and cell survival in vascular smooth muscle cells, and in cardiac myocyte function. Preliminary studies using a live animal model (with genetic ablation of Rap1 subtype A) suggest that Rap1A has a vital role in maintaining normal cardiac structure and function. Studies are underway to elucidate the molecular mechanism(s) of Rap1A signaling and function. We are also using intact blood vessels and explanted smooth muscle cells from blood vessels of wild-type and Rap1A-deficient mice to study the role of this GTPase in the vasculature.
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| Education |
| 2002 |
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Post-Doctoral Fellowship |
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Vascular Biology, Molecular Physiology |
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Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH |
| 1998 |
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Post-Doctoral Fellowship |
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Molecular and Cell Biology |
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The Ohio State University, Dept. of Internal Medicine, Columbus, OH |
| 1997 |
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PhD |
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Molecular, Cellular & Developmental Biology |
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The Ohio State University, Columbus, Ohio |
| 1988 |
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BA |
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Biology |
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The College of Wooster, Wooster, OH |
| Professional Experience |
| 2008- PRES |
Principal Investigator, Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio |
| 2002- 2008 |
Research Scientist, Davis Heart & Lung Research Institute, The Ohio State University |
| 1998- 2002 |
Postdoctoral Researcher/Fellow, Davis Heart & Lung Research Institute, The Ohio State University |
| 1997- 1998 |
Postdoctoral Researcher, Department of Internal Medicine, The Ohio State University |
| 1990- 1997 |
Graduate Research Associate, Program in Molecular, Cellular & Developmental Biology, The Ohio State University, Columbus, Ohio |
| 1988- 1990 |
Jr. Research Associate, Department of Psychiatry, MetroHealth Medical Center, Cleveland, Ohio |
| 1988- 1988 |
Laboratory Technician, Department of Preventive Veterinary Medicine, Food Animal Health Research Program, Ohio Agriculture Research & Development Center, Wooster, Ohio |
Research Interests
My research interests and activities are currently supported by Institutional internal funds, the American Heart Association, and the National Heart, Lung, and Blood Institute of the National Institutes of Health. The funds support research examining mechanisms of expression and cell-surface mobilization of endogenous micro-vascular smooth muscle G protein-coupled α2C-adrenergic receptors (α2C-ARs).
My colleagues and I identified the α2C-ARs as “stress-receptors” of the vascular sympathetic system. We have recently identified a novel signaling cascade in human vascular smooth muscle cells involving cyclic AMP, the Ras-related small G protein Rap1, actin binding protein filamin2, α2C-ARs, and the actin cytoskeleton. Current and future work involves studies to understand the role of Rap1 in the cardiovasculature and examination of stress-induced signature microRNAs and proteins in vascular smooth muscle cells. These studies will potentially lead to identification of physiologically relevant "vasculo-protective" players, conferring "stress-tolerance" to cells during cellular stress or vascular injury.
Broadly, these studies involve understanding the mechanisms behind alterations in peripheral vascular resistance, and peripheral vascular disorders. For example, in the cerebral circulation, in stroke, diabetes, hypercholesterolemia, hypertension, hypothermic response of the microvasculature seen in Raynaud’s phenomenon, secondary Raynaud’s associated with the devastating disease scleroderma, and hand-arm vibration syndrome.
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| Selected Publications |
| Eid AH, Chotani MA, Mitra S, Miller TJ, Flavahan S, Flavahan NA. 2008. Cyclic AMP acts through Rap1 and JNK signaling to increase expression of cutaneous smooth muscle α2C-adrenoceptors. Am J Physiol. Heart Circ Physiol. 295: H266-H272. PubMed ID: 18487435 |
| Eid A H, Maiti K, Mitra S, Chotani MA, Flavahan S, Bailey SR, Thompson-Torgerson CS, Flavahan NA. 2007. Estrogen increases smooth muscle expression of α2C-adrenoceptors and cold-induced constriction of cutaneous arteries. Am J Physiol. Heart Circ Physiol. 293: H1955-H1961. PubMed ID: 17644575 |
| Bayoumi MM, Alkheraije KA, El-Sayed O, Wisel S, Sarker K, Chotani MA, Zweier JL, Nuovo G, Goldschmidt-Clermont PJ, Hassanain H. 2007. Vascular hypertrophy caused by transgenic overexpression of profilin 1. J Biol Chem. 282:37632-37639. PubMed ID: 17942408 |
| Martin MM, Buckenberger JA, Jiang J, Malana GE, Nuovo GJ, Chotani M, Feldman DS, Schmittgen TD, Elton TS. 2007. The human angiotensin II type 1 receptor +1166 A/C polymorphism attenuates microRNA-155 binding. J Biol Chem. 282: 24262-24269. PubMed ID: 17588946 |
| Chotani MA, Mitra S, Eid AH, Han SA, Flavahan NA. 2005. Distinct cyclic AMP signaling pathways differentially regulate α2C-adrenoceptor expression: role in serum induction in human arteriolar smooth muscle cells. Am. J. Physiol. Heart Circ. Physiol, special “Translational Physiology” series article; 288: H69-H76. PubMed ID: 15345481 |
| Chotani MA, Mitra S, Su B Y, Flavahan S, Eid AH, Clark KR, Montague C, Paris H, Handy D E, Flavahan NA. 2004. Regulation of α2C-adrenoceptors in human vascular smooth muscle cells. Am. J. Physiol. Heart Circ. Physiol, special “Translational Physiology” series article; 286: H59-H67. PubMed ID: 12946937 |
| Chotani MA, Flavahan S, Mitra S, Daunt D, Flavahan NA. 2000. Silent α2C-adrenergic receptors enable cold-induced vasoconstriction in cutaneous arteries. Am. J. Physiol. Heart Circ. Physiol. 278:H1075-H1083. PubMed ID: 10749700 |
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