Orr Lab

Contact Us

LSU Health Shreveport
Department of Pathology
Biomedical Research Institute Rm 6-21
1501 Kings Hwy
Shreveport, LA 71103

 

Email: aorr@lsuhsc.edu
Office: (318) 675-5462 
Lab: (318) 675-5463
Fax: (318) 675-8144

A. Wayne Orr, PhD

Director and Professor
Division of Research, Department of Pathology and Translational Pathobiology
Director, Center for Cardiovascular Diseases and Sciences 
Professor, Department of Cell Biology and Anatomy, and Cellular and Molecular Physiology

Bachelor of Arts, Biology (1998) - Hendrix College
Ph.D., Pathology (2002) - University of Alabama, Birmingham
Post-Doctoral Fellow, Cardiovascular Research Center (2007) - University of Virginia

News

Zaki Al Yafeai received an American Heart Association Predoctoral Fellowship titled “Integrin affinity modulation in endothelial activation and atherosclerosis” in January 2019.  Congratulations Zaki!

The Orr lab was awarded an NIH R01 grant in December 2018 to continue their work on the role of EphA2 signaling in atherosclerotic fibroproliferative remodeling.  

Dr. Alexandra Finney successfully defended her dissertation titled “EphA2 regulates synthetic vascular smooth muscle fibroproliferative remodeling in experimental atherosclerosis” in November 2018.  Congratulations Dr. Finney.

As part of the new COBRE Center for Redox Biology and Cardiovascular Disease, Dr. Orr will run a Redox Molecular Signaling core providing services for molecular biology, cell culture models, and analytical redox measurements.

The Orr lab was awarded an NIH R01 grant renewal in December 2016 to continue their work on the role of endothelial cell integrin signaling in atherosclerotic plaque formation.  

The Orr lab was awarded an NIH R01 award in July 2016 to study the role of Nck adaptor protein signaling in endothelial cell activation during atherosclerotic plaque development.  

Research

Despite advances in treatments over the past several decades, cardiovascular disease remains the leading cause of death in developed countries worldwide. Atherosclerosis, a chronic inflammatory disease of the vessel wall, is responsible for more than 80% of all cardiovascular disease related deaths. Current models suggest that the local accumulation of low density lipoproteins (LDL, "bad cholesterol") in the vessel wall promotes an inflammatory response characterized by endothelial cell activation and leukocyte recruitment.  This early inflammatory response stimulates phenotypic changes in the underlying medial smooth muscle cells resulting in their proliferation and migration into the growing plaque, where they contribute both to plaque size and plaque stability.  Our lab studies how the arterial microenvironment, including soluble factors, vascular mechanics (stiffness, hemodynamics), and adhesive interaction, affects vascular cell function during atherosclerotic plaque formation. While current cardiovascular disease therapies target the systemic soluble risk factors, no therapeutics target the altered arterial microenvironment during atherosclerosis.  Through a better understanding of the molecular mechanisms regulating vascular cell function, we hope to identify novel therapeutic targets to limit cardiovascular disease. 

The subendothelial matrix in endothelial activation - Our research has shown an important role for matrix composition in modulating the cellular response to multiple atherogenic stimuli. Early during atherogenesis in vivo, wound-associated transitional matrix proteins (ex. fibronectin, fibrinogen) become deposited into the endothelial cell basement membrane. In vitro, these transitional matrix proteins enhance the ability of atherogenic stimuli, such as disturbed flow patterns and oxidized LDL, induce endothelial cell dysfunction, while components of the basement membrane (ex. collagen, laminin) limit endothelial cell dysfunction. We hypothesize that signals from cell-matrix interactions serve as a form of tissue memory, helping cells place atherogenic stimuli into a temporal context by indicating whether the tissue is actively remodeling.  Our current research seeks to understand the factors regulating matrix remodeling during atherogenesis (ex. hyperglycemia, oxidized LDL), to characterize how specific integrins (cell matrix receptors) contribute to endothelial activation in vitro and in vivo, and to characterize how integrin affinity modulation affects atherogenic endothelial activation.  

Nck adaptor proteins in atherogenic endothelial activation.  Work from our laboratory has shown that the Nck family of signaling adaptor proteins, Nck1 and Nck2, contribute to endothelial dysfunction under atherosclerotic conditions.  In response to shear or oxidant stress, Nck1/2 are recruited to tyrosine phosphorylated proteins at sites of cell-cell and cell-matrix adhesion, where they form specific signaling complexes to drive endothelial proinflammatory gene expression and vascular permeability.  Work from our group is currently characterizing the mechanisms regulating Nck1/2 recruitment following shear and oxidant stress and the role of individual Nck isoforms in endothelial activation in vitro and in vivo.   

Guidance Molecules in Atherogenic Remodeling - The ephrin and Eph family of cell-cell adhesion molecules are well characterized regulators of vascular and neuronal development and are implicated in numerous tissue remodeling responses in adult organisms. The Eph receptor EphA2 shows prominent expression in endothelial cells, macrophages, and synthetic smooth muscle cells, and we have demonstrated enhanced expression of EphA2 and its receptor ephrinA1 in both mouse models of atherosclerosis and human atherosclerotic plaques.  In endothelial cells, EphA2 signaling promotes proinflammatory endothelial activation, and EphA2 knockout mice show smaller plaques with reduced leukocyte recruitment.  However, EphA2 also contributes to smooth muscle growth, proliferation and extracellular matrix deposition, and plaques from EphA2 knockout mice show reduced markers of plaque stability.  Our current research seeks to characterize the dynamic interplay between smooth muscle EphA2 expression and matrix composition, determine the mechanisms by which EphA2 signaling affects smooth muscle proliferation and migration, and assess the role of EphA2 cell type-specific expression and signaling in atherosclerotic fibroproliferative remodeling.. 

Publications

Selected Publications

  1. Al-Yafaei Z.*, Yurdagul Jr. A.*, Peretik J.M., Alfaidi M., Murphy P., and A.W. Orr. (2018)  Endothelial a5ß1 integrins regulate fibronectin deposition, inflammation, and early atherosclerosis: a novel regulatory role for cell-derived fibronectin.  Arterioscler. Thromb. Vasc. Biol., 38: 2601-2614. *co-authors.
  2. Mravic M., Hu H., Lu Z., Bennett J.S., Sanders C.R., Orr A.W., and W.F. DeGrado. (2018) De novo designed transmembrane peptides activating the integrin a5ß1.  Prot. Eng. Design Select., 31: 181-190.
  3. Yuan S.*, Yurdagul Jr. A.*, Peretik J.M., Alfaidi M., Al Yafeai Z., Pardue S., Kevil C.G., and A.W. Orr. (2018)  Cystathionine y-lyase modulates flow-dependent vascular remodeling.  Arterioscler. Thromb. Vasc. Biol., 38: 2126-2136. *co-authors
  4. Senchenkova E.Y., Russell J., Vital S.A., Yildirim A., Orr A.W., Granger D.N., and F.N.E. Gavins.  (2018) A critical role for CD40 and VLA5 in angiotensin II-mediated thrombosis and inflammation in the microcirculation.  FASEB J., 32: 3448- 3456.
  5. Finney A.C., Funk S.D., Green J.M., Yurdagul A. Jr., Rana M.A., Pistorius R., Henry M., Yurochko A.D., Pattillo C.B., Traylor J.G., Chen J., Woolard M.D., Kevil C.G., and A.W. Orr.  (2017) EphA2 expression regulates inflammation and fibroproliferative remodeling in atherosclerosis.  Circulation, 136: 566-582. 
  6. Yurdagul Jr. A., Sulzmaier F., Chen X.L., Pattillo C.B., Schlaepfer D.D., and A.W. Orr.  (2016)  Focal adhesion kinase activates RSK to drive NF-kB activation and endothelial proinflammatory gene expression by oxidized LDL.  J. Cell Sci., 129: 1580-1591. PMID: 26906414.
  7. Yurdagul Jr. A., Finney A.C., Woolard M.D., and A.W. Orr.  (2016)  The Arterial Microenvironment: The Where and Why of Atherosclerosis.  Biochem J., 473: 1281-1295.  PMID: 27208212.
  8. Chen J.*, Green J.*, Yurdagul A. Jr., Albert P., McInnis, M.C., and A.W. Orr. (2015) avß3 integrins mediate flow-induced NF-kB activation, proinflammatory gene expression, and early atherogenic inflammation. Am. J. Pathol., 185: 2575-2589. * co-first authors.  PMID: 26212910.
  9. Chen J., Leskov I., Yurdagul A. Jr., Thiel B., Kevil C.G., Stokes K.Y., and A.W. Orr. (2015) Recruitment of the adaptor protein Nck to PECAM-1 couples oxidant stress to canonical NF-kB signaling and inflammation. Sci. Signal., 8: ra20.  PMID: 25714462.
  10. Yurdagul Jr. A., Green J., Albert P, McInnis M.C., Mazar A.P., and A.W. Orr.  (2014) a5ß1 integrin signaling mediates oxidized LDL-induced inflammation and early atherosclerosis.  Arterioscler. Thromb. Vasc. Biol., 34: 1362-1373.  PMID: 24833794.

Complete List of my Published Work in MyBibliography: LEARN MORE
 

Team

Wayne Orr, PhD

Principle Investigator 
aorr@lsuhsc.edu
The Orr Laboratory seeks to understand the role of the vessel microenvironment in regulating vascular cell function and the signaling mechanisms underlying this regulation.

Mabruka Alfaidi, PhD

Post-Doctoral Fellow
malfai@lsuhsc.edu
I study the role of the Nck family of adaptor proteins in endothelial cell activation during atherosclerotic plaque formation.

Dongdong Wang, PhD

Post-Doctoral Fellow
dwang2@lsuhsc.edu
I examine the role of cell-matrix interactions in endothelial cell priming and the role of atypical ubiquitination in integrin-dependent NF-kB activation.

Matt Scott

Post-Doctoral Fellow
mscot7@lsuhsc.edu
My project focuses on the roles of EphA2 receptor tyrosine kinase in smooth muscle proliferation and migration during atherosclerotic plaque formation. 

Elizabeth Cockerham

Lab Manager
ecocke@lsuhsc.edu
I investigate the role of EphA2 in the regulation of smooth muscle matrix deposition.  Using congenic animal models, I explore the role of cell adhesion receptors as they relate to atherosclerosis.  

Zaki Al-Yafaei

Graduate Student 
zalfae@lsuhsc.edu
My project focuses on studying the signaling mechanisms regulating integrin activation by oxidized LDL (oxLDL) and shear stress as well as the role of integrin activation in fibronectin matrix deposition. Additionally, I am investigating the role of integrin activation in endothelial function in vivo.

Umesh Bhattarai

Graduate Student
ubhatt@lsuhsc.edu
My project focuses on the roles of cell-matrix interactions in endothelial metabolism and mitochondrial function.

Brenna Pearson

Graduate Student
bpear1@lsuhsc.edu
My laboratory responsibilities center around tissue processing for histology. In addition, my research project examines the role of CSE expression in flow-induced vascular remodeling.

Kaylea Reeves

Undergraduate Student
kreev4@lsuhsc.edu
In addition to performing PCR genotyping for various mouse models, my work focuses on the regulation of Nck interactions in endothelial cells.

Milla Reddick

Undergraduate Student
mredd2@lsuhsc.edu
My laboratory responsibilities center around tissue processing for histology.  In addition, my research project examines the role of CSE expression in flow-induced vascular remodeling.

Elizabeth Matthews

Undergraduate Student
ematt7@lsuhsc.edu
My laboratory duties focus on general laboratory organization and maintenance.

ALUMNI

Jie Chen, Ph.D.
Current Status:
Post-doctoral Fellow,
LSU Health - Shreveport
 

Steven D. Funk
Current Status:
Post-doctoral Fellow,
Washington University


 

Arif Yurdagul, Jr., Ph.D.
Current Status:
Post-doctoral Fellow,
Columbia University

Positions

Post-doctoral Fellows

While we are not currently recruiting Post-doctoral Fellows, quality candidates will always be considered.  To enquire about opportunities, contact Dr. Orr at aorr@lsuhsc.edu.

Graduate Students

Graduate students interested in conducting research in the Orr lab should review the current laboratory research directions and contact Dr. Orr at aorr@lsuhsc.edu.

Undergraduate Research Assistants

We are not currently hiring any additional undergraduates. However, positions can become available during the summer.

Medical Students, Residents, and Fellows

The Orr laboratory has a number of research projects available for any Medical Students, Residents, and Fellows interested in performing atherosclerosis research. These projects can include the study of vascular cell biology, animal models of cardiovascular disease, and/or human atherosclerotic plaques.
 

Orr Lab