The Rabinovitch/Bland Lab

The Rabinovitch/Bland Lab

Rabinovitch/Bland Cardiopulmonary Research Laboratory
Vera Moulton Wall Center for Pulmonary Vascular Diseases
Department of Pediatrics (Cardiology and Neonatology)
Stanford University School of Medicine

2013 Highlights

Dr. Rabinovitch presented work from the laboratory at many high profile National and international meetings and conferences.  Her lectures introduced novel approaches to therapy for pulmonary hypertension and other cardiovascular disorders based upon basic research from the laboratory.  The themes of the lectures were related to the intersection of inflammation and genetics in the pathobiology of pulmonary hypertension.  She was invited to give the Keynote Lecture at the Arteriosclerosis, Thrombosis and Vascular Biology Annual Meeting, the 2nd Scientific Meeting of the Japanese Pulmonary Circulation Society in Tokyo, Japan and the Bioengineering Ontario-on-a-Chip MATCH Day at the University of Toronto, Canada.  She was a plenary speaker at the International Society of Heart and Lung Transplantation (ISHLT) Scientific Sessions in Montreal, Canada.   Dr. Rabinovitch also gave Research Rounds at the David Geffen School of Medicine at UCLA, Los Angeles, CA, and Cardiology Grand Rounds at the University of Pennsylvania Cardiovascular Institute, Philadelphia, Pennsylvania.  In addition she was invited as a guest speaker at the Gordon Research Conference in Vascular Cell Biology, Ventura, California, and participated in the Pathobiology Task Force at the 5th World Symposium on Pulmonary Hypertension, Nice, France.

Our Post Doctoral Fellows Presentations:

Postdoctoral fellow Nancy Ferreira Tojais, PhD won a Poster Presentation Award at the Gordon Research Conference on Elastin, Elastic Fibers and Microfibrils, held at the University of New England, Biddeford, ME, in July 2013, for her talk "BMP Plays a Positive and Decorin a Negative Role in Vascular Elastin Fiber Assembly" (Tojais NF, Lai Y-J, Rhodes CJ, Chen P-I, Cao A, Hopper RK, Wang L, Rabinovitch M).

The Rabinovitch group was well-represented at the 2013 International Conference of the American Thoracic Society (ATS) in Philadelphia, PA, in May.  Post doctoral fellow Nils Nickel, MD, presented a talk in the session on Novel Therapeutic Targets in Pulmonary Hypertension, titled “Elafin Restores Endothelial Cell Homeostasis in Pulmonary Arterial Hypertension.” (Nickel NP, Kaschwich M, Wang L, Spiekerkoetter E, Li GC, Rajagopalan V, Rabinovitch M.  Oral presentation in session A16).   Post doctoral fellow Pin-I Chen, PhD presented a poster on “Amphetamine induces pulmonary arterial endothelial cell dysfunction by increasing vulnerability to apoptosis and production of pro-inflammatory cytokines.” (Chen P-I, Perez-Martinez SU, Cao A, Rhodes CJ, Wang L, Rabinovitch M) and post doctoral fellow Nancy Ferreira Tojais, PhD, presented a poster on “Reduced BMPR2 causes abnormal elastin assembly.” (Tojais NF, Rhodes CJ, Cao A, Wang L, Rabinovitch M.).

2012:

NHLBI Translational Program Project Grant "Elafin Therapy of Lung Diseases" Awarded to a Team Led by Dr. Rabinovitch 

A research team led by Marlene Rabinovitch, MD, has been awarded a five-year, $10.8 million grant from the National Heart, Lung and Blood Institute for the study of a novel drug therapy’s ability to treat three distinct lung problems.  The project was sparked by exciting preclinical data indicating that the elastase inhibitor elafin can be used to treat three of the most challenging lung conditions: pulmonary hypertension (project led by Dr Rabinovitch), ventilator-induced injury of the immature lung (led by Dr Bland) and lung transplant rejection (led by Dr. Mark Nicolls). A Biomarker Core, directed by Drs. Carlos Milla and Roham Zamanian, will develop bioassays to assess treatment efficacy for these diseases in humans and help stratify patients for future clinical trials.  Read more: Inside Stanford Medicine story

NHLBI Grant Awarded to Fund Use of iPS Cells to Study Pulmonary Hypertension

Marlene Rabinovitch, Michael Snyder (Genetics) and Joe Wu (CV Medicine) were awarded  $9.1 million over five years to study the inherited causes of pulmonary hypertension, using induced pluripotent stem cells (iPSCs) as surrogates for the disease.  The team will create blood vessel cells from patients with pulmonary hypertension to explore the hereditary causes of the condition. Key to the study is a collaboration with the Pulmonary Hypertension Breakthrough National Network, which will enable the Stanford team to work with cells from diseased lungs that were removed during a transplant operation. The studies proposed will not only help uncover the genetic basis for pulmonary hypertension but will improve our understanding of the biological basis of the disease, which is necessary to develop diagnostic tools and personalized treatment strategies.  Read more: Inside Stanford Medicine story

Selected Featured Research - Commentaries, Covers, Media:

Tacrolimus shows promise in PAH models: The article "FK506 Activates BMPR2 Signaling, Rescues Endothelial Dysfunction, Reverses Pulmonary Hypertension"  by Edda Spiekerkoetter and coworkers from the Rabinovitch Lab was featured as a Research Highlight by Nature Reviews Drug Discovery  (Nature Reviews Drug Discovery 12, 666 )

Targeting Elastase in Bronchopulmonary Dysplasia:  The article "Inhibiting Lung Elastase Activity Enables Lung Growth in Mechanically Ventilated Newborn Mice" from the laboratory of Dr Richard Bland, was featured in an editorial in the American Journal of Respiratory and Critical Care Medicine. The author, Rory E. Morty, PhD, said: "In this issue of the Journal (pp. 537) Hilgendorff and coworkers (8) make the exciting observation that intratracheal administration of elafin ... concomitantly with mechanical ventilation of 5-day old full-term mouse pups with oxygen-rich (40% O2) gas protected against the deleterious effects of mechanical ventilation with oxygen-rich gas on alveolar development. The beauty of the experimental model ...is the extent of recapitulation of the clinical scenario: the mechanical ventilation of neonates during a critical phase of late lung development (in this case, the saccular stage), with relatively moderate levels of normobaric oxygen, compared with, for example, classical hyperoxia-based animal models of BPD, in which oxygen concentrations of 85 to 95% O2 are employed, without mechanical ventilation."
Editorial: Morty RE, American Journal of Respiratory and Critical Care Medicine Vol 184. pp. 496-497 (2011);

Article: Inhibiting Lung Elastase Activity Enables Lung Growth in Mechanically Ventilated Newborn Mice. Hilgendorff A, et al., Am J Respir Crit Care Med. 2011; Sep 1;184(5):537-46.

BMP promotes motility and represses growth of smooth muscle cells by activation of tandem Wnt pathways:   The article was featured in the January 10, 2011 edition of Biobytes (The Rockefeller University Press). Vinicio de Jesus Perez and Marlene Rabinovitch describe the signaling pathways that regulate blood vessel repair. The article presents a novel cell-signaling paradigm in which bone morphogenetic protein 2 (BMP-2) consecutively and interdependently activates the wingless (Wnt)–ß-catenin and Wnt–planar cell polarity (PCP) signaling pathways to facilitate vascular smooth muscle motility while simultaneously suppressing growth. de Jesus Perez VA, et al., Journal of Cell Biology 2010; 192 (1): 171-188.

Listen to the podcast: http://jcb.rupress.org/content/192/1/171/suppl/DC2

BMP-2 recruits the PDZ and DEP domains of Dvl to activate RhoA and Rac1 and induce hPAEC motility:   Mutations in the bone morphogenetic protein receptor (BMPRII) are associated with idiopathic pulmonary hypertension, which is characterized by a loss of pulmonary artery endothelial cells (PAECs).  Ednothelial cell transfected with DEP+ Dvl We found that BMP-2 promotes survival, proliferation and migration (shown) of PAECs through activation of both canonical and non-canonical Wnt signaling pathways.
Right: A confocal image of a cell nucleofected with GFP-tagged Dvl construct, starved for 24 hours and incubated with BMP-2.   Blue, DAPI-stained nucleus; Green, GFP tagged Dvl; Red, Phalloidin-labeled actin.  
From de Jesus Perez VA, et al., Journal of Cell Biology 2009; 184(1): 83-99, featured in The Cell Biology of Disease, Journal of Cell Biology Special Issue 2009

 

In The Spotlight

Dr. 
Rabinovitch

Marlene Rabinovitch M.D.
Dwight and Vera Dunlevie Professor of Pediatrics
Professor (by courtesy) of Developmental Biology
Research Director, Vera Moulton Wall Center for Pulmonary Vascular Disease
Stanford University School of Medicine Research interests.

Richard Bland

Richard D. Bland, M.D.

Professor of Pediatrics
Stanford University School of Medicine

Research interests.

Recently Published

FK506 Activates BMPR2 Signaling, Rescues Endothelial Dysfunction, Reverses Pulmonary Hypertension.
Spiekerkoetter E,  Tian X, Cai J, Hopper RK, Sudheendra D, Li CG, El-Bizri N, Sawada H, Haghighat R, Chan R, Haghighat L, de Jesus Perez V,  Wang L, Reddy S, Zhao M, Bernstein D, Solow-Cordero DE, Beachy PA, Wandless TJ, ten Dijke and Rabinovitch M.  Journal of Clinical Investigation 2013 Aug 1;123(8):3600-13 (PubMedID: 23867624)

Loss of Adenomatous Poliposis Coli-α3 Integrin Interaction Promotes Endothelial Apoptosis in Mice and Humans.
de Jesus Perez VA, Yuan K, Orcholski ME, Sawada H, Zhao M, Li CG, Tojais NF, Nickel NP, Rajagopalan V, Spiekerkoetter E, Wang L, Dutta R, Bernstein D, Rabinovitch M. Circ Res. 2012 Dec 7;111(12):1551-64 (PubMedID: 23011394)

Neonatal mice genetically modified to express the elastase inhibitor elafin are protected against the adverse effects of mechanical ventilation on lung growth.
Hilgendorff A, Parai K, Ertsey R, Juliana Rey-Parra G, Thébaud B, Tamosiuniene R, Jain N, Navarro EF, Starcher BC, Nicolls MR, Rabinovitch M, Bland RD. Am J Physiol Lung Cell Mol Physiol. 2012 Aug;303(3):L215-27.
(PubMedID: 22683569)

Disruption of PPARgamma /ß-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival.
Alastalo TP, Li M, Perez Vde J, Pham D, Sawada H, Wang JK, Koskenvuo M, Wang L, Freeman BA, Chang HY, Rabinovitch M. J Clin Invest. 2011; 121 (9): 3735-46
(PubMedID: 21821917)

Inhibiting lung elastase activity enables lung growth in mechanically ventilated newborn mice.
Hilgendorff A, Parai K, Ertsey R, Jain N, Navarro EF, Peterson JL, Tamosiuniene R, Nicolls MR, Starcher BC, Rabinovitch M, Bland RD. Am J Respir Crit Care Med. 2011; Sep 1;184(5):537-46.
(PubMedID: 21562133)

Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions.
Kim YM, Haghighat L, Spiekerkoetter E, Sawada H, Alvira CM, Wang L, Acharya S, Rodriguez-Colon G, Orton A, Zhao M, Rabinovitch M. Am J Pathol. 2011; 179 (3): 1560-72.
(PubMedID: 21763677)

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