Brief Bio

After receiving a Bachelor of Science degree in Chemistry from Mount Alison University, Dr. Walker pursued a B.Ed. from Ottawa University and was subsequently employed as a board-certified high school chemistry teacher. After teaching for two years she began graduate work focused on cardio-respiratory physiology at Queen’s University in Kingston, Ontario, Canada. Dr. Walker’s postdoctoral training in cell biology at Duke University focused on receptor signaling pathways; in particular those of G protein-coupled receptors (GPCRs). GPCRs are the largest family of cell surface receptors and more than half of all medically prescribed drugs target their function. Dr. Walker’s research, which focuses on understanding the cellular pathophysiological mechanisms that underlie lung disease (in particular asthma) has been independently funded since 2004, and she currently holds the Duke University rank of Professor in Nursing and Pulmonary Medicine. Dr. Walker is an expert in GPCR regulation by beta-arrestin proteins and the application of this to the pathophysiology of asthma. Currently, Dr. Walker’s research focus includes the study of novel β-2-adrenoceptor ligands and biased signaling in the treatment of asthma. This research holds great potential to rapidly improve quality of life for asthmatics. Dr. Walker has published 41 peer-reviewed basic research, 5 review or opinion articles and 2 book Chapters, and has been an invited speaker at numerous seminar forums both Nationally and Internationally. She has been recognized by her peers with ATS-sponsored awards such as the Ann Woolcock memorial and ATS Young Investigator awards. Dr. Walker teaches Physiology to Nursing Students using a deep learning approach which asks students to comprehend concepts rather than memorize facts. This approach facilitates retention of information and development of critical thinking skills. Dr. Walker has received the Outstanding MSN Faculty and DUNAP Faculty of the Year awards.

Academic Program Affiliations

Education

Clinical Interests

Broadly, my research focuses on the role for G protein-coupled receptors in the pathophysiology of asthma. Asthma is a complex disease characterized by airway inflammation, hyperresponsiveness and remodeling. G protein-coupled receptors figure largely in the pathology and treatment of this disease. For example, beta-agonists, the rescue medication inhaled by asthmatics, act at airway smooth muscle beta2-adrenergic receptors (β2-AR) to relax the airways. However, excessive use of beta-agonists has been associated with clinical worsening of asthma control and increased mortality. β2-ARs can signal through two well characterized and independent signaling pathways; a G protein-dependent pathway and a beta-arrestin-dependent pathway. Previously we showed that mice lacking beta-arrestin-2 do not develop the symptoms of allergic airway inflammatory disease and that T cell and eosinophil migration to the lung is impaired in these mice. Similarly, others have shown that the asthma phenotype is significantly reduced in mice lacking global expression of β2-ARs. Thus, we hypothesize that the beta-arrestin-dependent signaling arm, downstream of the β2-AR, is responsible for promoting the asthma phenotype. The translational relevance of this work is high given that the determination of the signaling pathway that is utilized by β2-ARs can be influenced by the molecular signature of the agonist. Thus, our work could lead to the discovery of a β2-AR ligand that bronchodilates the airways without promoting asthma symptoms. In addition to transducing β2-AR-mediated signaling to promote asthma, we hypothesize that beta-arrestin-2 also mediates chemokine receptor signaling and thus, the inflammatory component of asthma. Chemokines, released in response to allergens, dictate the migration of immune cells to the lung in asthma and chemokine receptors are known to signal via both the G-dependent and beta-arrestin-dependent pathways.

Awards and Honors

• 2014 Faculty of the Year, Duke University Nurse Anesthesia Program

• 2014 Outstanding MSN Faculty Award, Duke University School of Nursing

• 2009 ATS-Appointed Young Investigator to the 49th Annual Japanese Respiratory Society Meeting, American Thoracic Society

• 2004 Ann Woolcock Memorial Award, ATS - American Thoracic Society

• 1999 Fellowship, Medical Council of Canada

• 1997 Fellowship, Canadian Lung Association/Medical Research Council

• 1996 Abrahams’ Prize in Physiology, Queen’s University

• 1995 Ontario Graduate Student Award

• 1995 Queen's Graduate Award, Queen’s University

• 1994 Dean's Award, Queen's University

• 1994 Queen's Graduate Fellowship, Queen’s University

• 1993 Fellowship, Ontario Thoracic Society

• 1992 Ontario Graduate Student Award

• 1991 Dean's Award, Queen’s University

• 1991 Fellowship, Ontario Thoracic Society

• 1987 Murray Sears Memorial Prize in Chemistry, Mount Allison University

• 1985 Dean's Scholarship, Academic, Mount Allison University

• 1985 Dean's Scholarship, Athletic Achievement, Mount Allison University

• 1984 Ralph Pickard Bell Entrance Scholarship, Mount Allison University

• 1983 Carleton Board of Education Bursary for Gifted Students

Areas of Expertise

• Physiology

Areas of Interest

• Physiology, G protein-coupled receptor signaling, Beta-arrestin role in asthma pathogenesis, optimizing beta-2-adrenergic receptor biased signaling in asthma

Representative Publications

• 2015 -- Pubmed # 26103985 Pera, T., Hegde, A., Deshpande, D. A., Morgan, S. J., Tiegs, B. C., Theriot, B. S., Choi, Y. H., Walker, J. K., Penn, R. B. Specificity of arrestin subtypes in regulating airway smooth muscle G protein-coupled receptor signaling and function. FASEB J. October, 2015; 29(10); 4227-35 PMCID: PMC4566941

• 2015 -- Pubmed # 25569510 Chen, M., Hegde, A., Choi, Y. H., Theriot, B. S., Premont, R. T., Chen, W., Walker, J. K. Genetic Deletion of β-Arrestin-2 and the Mitigation of Established Airway Hyperresponsiveness in a Murine Asthma Model. Am J Respir Cell Mol Biol. September 1, 2015; 53(3); 346-54 PMCID: PMC4566063

• 2015 -- Pubmed # 25658948 Hegde, A., Strachan, R. T., Walker, J. K. Quantification of Beta adrenergic receptor subtypes in Beta-arrestin knockout mouse airways. PLoS One. February 6, 2015; 10(2); e0116458

• 2014 -- Pubmed # 24907413 Walker, J. K., DeFea, K. A. Role for β-arrestin in mediating paradoxical β2AR and PAR2 signaling in asthma. Curr Opin Pharmacol. June 1, 2014; 16C 142-147

• 2014 -- Pubmed # 24888515 Walker, J. K., Fisher, J. T. Editorial overview: Respiratory: GPCR signaling and the lung. Curr Opin Pharmacol. June 1, 2014; 16 iv-vi

• 2014 -- Pubmed # 24292841 Penn, R. B., Bond, R. A., Walker, J. K. GPCRs and Arrestins in Airways: Implications for Asthma. Handb Exp Pharmacol. 2014; 219 387-403

• 2013 -- Pubmed # 23991664 Forkuo, G. S., Thanawala, V. J., Al-Sawalha, N., Bond, R. A., Walker, J. K. Reply: Adverse effects of long-acting beta-agonists on airway hyperresponsiveness. Am J Respir Cell Mol Biol. September, 2013; 49(3); 502

• 2013 -- Pubmed # 23204390 Thanawala, V. J., Forkuo, G. S., Al-Sawalha, N., Azzegagh, Z., Nguyen, L. P., Eriksen, J. L., Tuvim, M. J., Lowder, T. W., Dickey, B. F., Knoll, B. J., Walker, J. K., Bond, R. A. β2-Adrenoceptor agonists are required for development of the asthma phenotype in a murine model. Am J Respir Cell Mol Biol. February, 2013; 48(2); 220-9

• 2013 -- Pubmed # 23408785 Walker, J. K., Kraft, M., Fisher, J. T. Assessment of murine lung mechanics outcome measures: alignment with those made in asthmatics. Front Physiol. February, 2013; 3(491); PMCID: PMC3569663

• 2012 -- Pubmed # 23012429 Nichols, H. L., Saffeddine, M., Theriot, B. S., Hegde, A., Polley, D., El-Mays, T., Vliagoftis, H., Hollenberg, M. D., Wilson, E. H., Walker, J. K., DeFea, K. A. β-Arrestin-2 mediates the proinflammatory effects of proteinase-activated receptor-2 in the airway. Proc Natl Acad Sci U S A. October, 2012; 109(41); 16660-5 PMCID: PMC3478622

• 2012 -- Pubmed # 22013997 Lin, R., Degan, S., Theriot, B. S., Fischer, B. M., Strachan, R. T., Liang, J., Pierce, R. A., Sunday, M. E., Noble, P. W., Kraft, M., Brody, A. R., Walker, J. K. Chronic treatment in vivo with β-adrenoceptor agonists induces dysfunction of airway β(2) -adrenoceptors and exacerbates lung inflammation in mice. Br J Pharmacol. April, 2012; 165(7); 2365-77 PMCID: PMC3413869

• 2011 -- Pubmed # 21175591 Walker, J. K., Penn, R. B., Hanania, N. A., Dickey, B. F., Bond, R. A. New perspectives regarding β(2) -adrenoceptor ligands in the treatment of asthma. Br J Pharmacol. May, 2011; 163(1); 18-28 PMCID: PMC3085865

• 2011 -- Pubmed # 20348208 Pastva, A. M., Walker, J. K., Maddox, L. A., Mukherjee, S., Giamberardino, C., Hsia, B., Potts, E., Zhu, H., Degan, S., Sunday, M. E., Lawson, B. L., Korfhagen, T. R., Schwartz, D. A., Eu, J. P., Foster, W. M., McMahon, T. J., Que, L., Wright, J. R. Nitric oxide mediates relative airway hyporesponsiveness to lipopolysaccharide in surfactant protein A-deficient mice. Am J Respir Cell Mol Biol. February, 2011; 44(2); 175-84 PMCID: PMC3049231

• 2010 -- Pubmed # 19805483 Hollingsworth, J. W., Theriot, B. S., Li, Z., Lawson, B. L., Sunday, M., Schwartz, D. A., Walker, J. K. Both hematopoietic-derived and non-hematopoietic-derived {beta}-arrestin-2 regulates murine allergic airway disease. Am J Respir Cell Mol Biol. September, 2010; 43(3); 269-75 PMCID: PMC2933545

• 2010 -- Pubmed # 20399707 Dickey, B. F., Walker, J. K., Hanania, N. A., Bond, R. A. beta-Adrenoceptor inverse agonists in asthma. Curr Opin Pharmacol. June, 2010; 10(3); 254-9 PMCID: PMC2905467

• 2008 -- Pubmed # 18337459 Deshpande, D. A., Theriot, B. S., Penn, R. B., Walker, J. K. Beta-arrestins specifically constrain beta2-adrenergic receptor signaling and function in airway smooth muscle. FASEB J. July, 2008; 22(7); 2134-41 PMCID: PMC3514410

• 2008 -- Pubmed # 18587448 Ryu, H., Walker, J. K., Kim, S., Koo, N., Barak, L. S., Noguchi, T., Kang, B. Y., Kim, K. Regulation of M2-type pyruvate kinase mediated by the high-affinity IgE receptors is required for mast cell degranulation. Br J Pharmacol. July, 2008; 154(5); 1035-46 PMCID: PMC2451040

• 2007 -- Pubmed # 17969115 Driehuys, B., Walker, J., Pollaro, J., Cofer, G. P., Mistry, N., Schwartz, D., Johnson, G. A. 3He MRI in mouse models of asthma. Magn Reson Med. November, 2007; 58(5); 893-900 PMCID: PMC2746053

• 2007 -- Pubmed # 17255472 Vincent, S. G., Waddell, A. E., Caron, M. G., Walker, J. K., Fisher, J. T. A murine model of hyperdopaminergic state displays altered respiratory control. FASEB J. May, 2007; 21(7); 1463-71

• 2006 -- Pubmed # 16809636 Garantziotis, S., Brass, D. M., Savov, J., Hollingsworth, J. W., McElvania-TeKippe, E., Berman, K., Walker, J. K., Schwartz, D. A. Leukocyte-derived IL-10 reduces subepithelial fibrosis associated with chronically inhaled endotoxin. Am J Respir Cell Mol Biol. December, 2006; 35(6); 662-7 PMCID: PMC2643294

• 2006 -- Pubmed # 16474097 Walker, J. K., Ahumada, A., Frank, B., Gaspard, R., Berman, K., Quackenbush, J., Schwartz, D. A. Multistrain genetic comparisons reveal CCR5 as a receptor involved in airway hyperresponsiveness. Am J Respir Cell Mol Biol. June, 2006; 34(6); 711-8

• 2005 -- Pubmed # 15917400 Raehal, K. M., Walker, J. K., Bohn, L. M. Morphine side effects in beta-arrestin 2 knockout mice. J Pharmacol Exp Ther. September, 2005; 314(3); 1195-201

• 2005 -- Pubmed # 15833764 Savov, J. D., Brass, D. M., Lawson, B. L., McElvania-Tekippe, E., Walker, J. K., Schwartz, D. A. Toll-like receptor 4 antagonist (E5564) prevents the chronic airway response to inhaled lipopolysaccharide. Am J Physiol Lung Cell Mol Physiol. August, 2005; 289(2); L329-37

• 2004 -- Pubmed # 15020293 Hollingsworth 2nd, J. W., Cook, D. N., Brass, D. M., Walker, J. K., Morgan, D. L., Foster, W. M., Schwartz, D. A. The role of Toll-like receptor 4 in environmental airway injury in mice. Am J Respir Crit Care Med. July, 2004; 170(2); 126-32

• 2004 -- Pubmed # 14565944 Walker, J. K., Gainetdinov, R. R., Feldman, D. S., McFawn, P. K., Caron, M. G., Lefkowitz, R. J., Premont, R. T., Fisher, J. T. G protein-coupled receptor kinase 5 regulates airway responses induced by muscarinic receptor activation. Am J Physiol Lung Cell Mol Physiol. February, 2004; 286(2); L312-9

• 2003 -- Pubmed # 12925697 Walker, J. K., Fong, A. M., Lawson, B. L., Savov, J. D., Patel, D. D., Schwartz, D. A., Lefkowitz, R. J. Beta-arrestin-2 regulates the development of allergic asthma. J Clin Invest. August, 2003; 112(4); 566-74 PMCID: PMC171386

• 2003 -- Pubmed # 12626335 Whitehead, G. S., Walker, J. K., Berman, K. G., Foster, W. M., Schwartz, D. A. Allergen-induced airway disease is mouse strain dependent. Am J Physiol Lung Cell Mol Physiol. July, 2003; 285(1); L32-42

• 2002 -- Pubmed # 11978791 Shetzline, M. A., Walker, J. K., Valenzano, K. J., Premont, R. T. Vasoactive intestinal polypeptide type-1 receptor regulation. Desensitization, phosphorylation, and sequestration. J Biol Chem. July, 2002; 277(28); 25519-26

• 2000 -- Pubmed # 10915639 Walker, J. K., Gainetdinov, R. R., Mangel, A. W., Caron, M. G., Shetzline, M. A. Mice lacking the dopamine transporter display altered regulation of distal colonic motility. Am J Physiol Gastrointest Liver Physiol. August, 2000; 279(2); G311-8

• 2000 -- Pubmed # 10655494 Claing, A., Perry, S. J., Achiriloaie, M., Walker, J. K., Albanesi, J. P., Lefkowitz, R. J., Premont, R. T. Multiple endocytic pathways of G protein-coupled receptors delineated by GIT1 sensitivity. Proc Natl Acad Sci U S A. February, 2000; 97(3); 1119-24 PMCID: PMC15541

• 1999 -- Pubmed # 10624964 Gainetdinov, R. R., Bohn, L. M., Walker, J. K., Laporte, S. A., Macrae, A. D., Caron, M. G., Lefkowitz, R. J., Premont, R. T. Muscarinic supersensitivity and impaired receptor desensitization in G protein-coupled receptor kinase 5-deficient mice. Neuron. December, 1999; 24(4); 1029-36

• 1999 -- Pubmed # 10531354 Walker, J. K., Premont, R. T., Barak, L. S., Caron, M. G., Shetzline, M. A. Properties of secretin receptor internalization differ from those of the beta(2)-adrenergic receptor. J Biol Chem. October, 1999; 274(44); 31515-23

• 1999 -- Pubmed # 10030450 Walker, J. K., Jennings, D. B. Respiratory effects of pressor and depressor agents in conscious rats. Can J Physiol Pharmacol. June, 1999; 76(7-8); 707-14

• 1999 -- Pubmed # 10198406 Walker, J. K., Peppel, K., Lefkowitz, R. J., Caron, M. G., Fisher, J. T. Altered airway and cardiac responses in mice lacking G protein-coupled receptor kinase 3. Am J Physiol. April, 1999; 276(4 Pt 2); R1214-21

• 1998 -- Pubmed # 9795743 Walker, J. K., Jennings, D. B. Ventilatory and metabolic effects of hypercapnia in conscious rats: AVP V1 receptor block. Can J Physiol Pharmacol. April, 1998; 76(4); 361-6

• 1998 -- Pubmed # 9506976 Shetzline, M. A., Premont, R. T., Walker, J. K., Vigna, S. R., Caron, M. G. A role for receptor kinases in the regulation of class II G protein-coupled receptors. Phosphorylation and desensitization of the secretin receptor. J Biol Chem. March, 1998; 273(12); 6756-62

• 1997 -- Pubmed # 9128905 Walker, J. K., Lawson, B. L., Jennings, D. B. Breath timing, volume and drive to breathe in conscious rats: comparative aspects. Respir Physiol. March, 1997; 107(3); 241-50

• 1996 -- Pubmed # 9028585 Walker, J. K., Jennings, D. B. Ventilatory effects of angiotensin and vasopressin in conscious rats. Can J Physiol Pharmacol. November, 1996; 74(11); 1258-64

• 1995 -- Jennings, D. B., Walker, J. K. L.,, Ohtake, P. J. Central effects and interactions of the renin-angiotensin system and vasopressin on ventilation and PaCO2 In Ventral Brainstem Mechanisms and Control Functions, edited by Trouth, O., R. Millis, H. Kiwull-Schöne, & M.E. Schläfke 1995; pp. 203-224. New York: Marcel Dekker, Inc..

• 1996 -- Pubmed # 8964741 Overgaard, C. B., Walker, J. K., Jennings, D. B. Respiration during acute hypoxia: angiotensin- and vasopressin-receptor blocks. J Appl Physiol (1985). March, 1996; 80(3); 810-7

• 1995 -- Pubmed # 8567518 Walker, J. K., Jennings, D. B. During acute hypercapnia vasopressin inhibits an angiotensin drive to ventilation in conscious dogs. J Appl Physiol (1985). September, 1995; 79(3); 786-94

• 1994 -- Pubmed # 7928878 Walker, J. K., Jennings, D. B. Angiotensin mediates stimulation of ventilation after vasopressin V1 receptor blockade. J Appl Physiol (1985). June, 1994; 76(6); 2517-26

• 1993 -- Pubmed # 8482661 Ohtake, P. J., Walker, J. K., Jennings, D. B. Renin-angiotensin system stimulates respiration during acute hypotension but not during hypercapnia. J Appl Physiol (1985). March, 1993; 74(3); 1220-8

Grant Funding (selected)

• Mechanisms that Direct Airway Remodeling in Obese Asthma  
  NIH-NHLBI
  HL213214
  09/2017-06/2021
  Role: Co-Investigator
  Obesity contributes to asthma pathobiology. The primary goal of this project is to define mechanisms whereby leptin and glucagon-like peptide-1 modulate fibrotic processes and IL-13 signaling in airway fibroblasts in early-onset, obese asthma.

• Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease  
  Cedars Sinai Medical Center
  001073456
  06/2014-05/2015
  Role: PI
  

• Optimizing Beta-Adrenoceptor Signaling Bias in Asthma  
  National Institutes of Health
  1R01-AI110007-01A1
  06/2014-05/2019
  Role: Principal Investigator
  Project Goals: We propose studies to solve the “beta-2 adrenoceptor paradox” in asthma by establishing the cell-specific role of beta-2 adrenoceptor signaling pathways in regulating the asthma phenotype, and identifying from among current and newly generated beta-2 adrenoceptor ligands or modulators those with biased signaling properties that are optimal in their ability to antagonize pathogenic beta-2 adrenoceptor signaling via arrestins, yet promote beneficial G protein signaling.

• Host factors in regulation of inflammatory and fibroproliferative lung disease  
  NIH-NHLBI
  08/2012-07/2017
  Role: Animal Core Principal Investigator
  Project Goals: The primary goal of this project is to determine the mechanism by which host factors interact with lung injury or allergen exposure to promote lung inflammation and fibrosis.

• Mechanisms of Beta-blocker Induced Improvements in Asthma  
  NIH-NHLBI
  AI079236-03
  06/2013-05/2018
  Role: Co-Principal Investigator
  Project Goals: The primary goal of this project is to determine the mechanism of the proasthmatic effect of β2AR signaling.

• Modeling beta2-adrenergic receptor desensitization in mouse airway smooth muscle  
  Aerie Pharmaceuticals
  03/2012-02/2013
  Role: Principal Investigator
  Project Goals: The overall goal of this research is to evaluate the immediate and prophylactic effects of Aerie Pharmaceutical compounds (rho-kinase super inhibitors) on asthmatic inflammation and associated airway hyperresponsiveness in mice.

• Arrestin selectivity for GPCRs in airway smooth muscle  
  NIH-NHLBI
  R01-HL093103-01A2
  04/2010-03/2014
  Role: Co-Principal Investigator
  Project Goals: The primary goal of this project is to delineate the functional selectivity of β arrestin-mediated desensitization of pro-and anti-contractile GPCRs in airway smooth muscle.

• T cell metabolism as a determinant of differentiation in allergic asthma  
  NIH-NHLBI
  R01-HL108006-01
  04/2010-03/2015
  Role: Collaborator Investigator
  Project Goals: The primary goal of this project is to delineate the mechanism by which glucose transporter function influences T cell metabolism and function in allergic asthma.

• T cell function in asthma depends on a novel signaling pathway  
  NIH-NHLBI
  R01-HL084123
  02/2008-01/2013
  Role: Principal Investigator
  Project Goals: The primary goal of this project is to delineate the mechanism by which beta arrestin-2 regulates T cell chemotaxis in asthma.

• Modeling beta2-adrenergic receptor desensitization in mouse airway smooth muscle  
  Sepracor, Inc.
  10/2005-12/2007
  Role: Principal Investigator
  Project Goals: The overall goal of this research is to develop a mouse model of beta2-adrenergic receptor desensitization in airway smooth muscle and to test the effects of levalbuterol in this model. 2-adrenergic receptor dysfunction occurs in human asthmatics precipitating morbidity and mortality.

• Mouse Models of Heart, Lung and Blood Diseases  
  NIH-NHLBI
  U01 HL66611 renewal
  09/2004-08/2008
  Role: Principal Investigator (subcontract: David A. Schwartz)
  Project Goals: The overall goal of this research is to provide new resources for identifying the genes underlying lung disorders by examining the physiologic and biologic response of the lung to complementary challenges in ENU mutagenized mice.

• The role for beta-arrestin-2 in regulating lung inflammatory disorders  
  Veterans Administration Merit Review Entry Program
  07/2004-06/2007
  Role: Principal Investigator
  Project Goals: The overall goal of this project is to understand the mechanisms by which beta-arrestin-2 regulates the development of allergen induced airway disease

• Modeling beta-2-adrenergic receptor desensitization in mouse airway smooth muscle  
  Norak Biosciences
  07/2004-01/2005
  Role: Principal Investigator
  Project Goals: The overall goal of this research is to develop a mouse model of beta2-adrenergic receptor desensitization in airway smooth muscle. This phenomenon occurs in human asthmatics precipitating increased morbidity and mortality.

• The Pathogenesis and Genetics of Environmental Asthma  
  NIH/NIEHS
  5 U19 ES012496-05
  09/2003-06/2009
  Role: Administrative Core Consultant
  The overall theme of this PPG is to understand further the pathogenesis and genetics of asthma by studying environmental airway disease.

• Mouse Models of Heart, Lung and Blood Diseases  
  NIH-NHLBI
  U01 HL66611
  09/2000-09/2004
  Role: Consultant
  Project Goals: The overall goal of this research is to provide new resources for identifying the genes underlying lung disorders by examining the physiologic and biologic response of the lung to complementary challenges in ENU mutagenized mice

• Role of GPCR regulatory mechanisms in the pathophysiology of asthma  
  Sandler Program for Asthma Research
  07/2000-06/2004
  Role: Co-Principal Investigator
  Project Goals: The major goals of this project are to screen mice with a genetic deletion of a G protein-coupled receptor kinase or an arrestin protein for altered airway responsiveness or airway inflammation in the context of allergic or non-allergic asthma.