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

Dr. Rabinovitch to give the 2016 J. Burns Amberson Lecture at the American Thoracic Society's annual meeting

In what is considered to be the highest honor accorded by the ATS, Dr. Rabinovitch has been selected to give the 2016 J. Burns Amberson Lecture at the American Thoracic Society’s annual meeting in San Francisco on May 15. The lecture honors the late Dr. Amberson, an international authority on chest disease and tuberculosis, and recognizes “a career of major lifetime contributions to clinical or basic pulmonary research and/or clinical practice.”

From a press release: “In her extraordinary, 30-year career, Dr. Rabinovitch has made incredible contributions to our understanding of congenital and acquired pulmonary hypertension,” said Hugh O’Brodovich, MD, the Adalyn Jay Physician-in-Chief at Packard Children's and Professor of Pediatrics at Stanford University School of Medicine. “She is recognized throughout the world of pediatric and adult cardiology as an amazing scientist, teacher, and clinician. Through the Amberson Lecture, she will no doubt bring great inspiration to current and future leaders in this field, and we are extremely proud to call her one of our own.” (Full story: BusinessWire Press Release 03/30/16)

2015 Highlights


Dr. Pfeffer, Dr. Rabinovitch (2nd from left), and Green family members (October 2015)

Dr. Rabinovitch was the 32nd Annual Laurence H. Green Memorial Lecturer at the Medical Grand Rounds at the Peter Bent Brigham Hospital Harvard Medical School. Boston. The lecture addressed "Crossing the Intersection Between Genetics and Inflammation to Find New Treatments for Pulmonary Arterial Hypertension". During this visit, Dr. Rabinovitch was also invited to present the Cardiovascular Ground Rounds discussing "Novel Functions of PPARgamma in the Vascular Response to Injury".

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 spoke at the Joint Symposium of the Excellence Cluster Cardio-Pulmonary System (ECCPS), the 2014 International Conference of the American Thoracic Society (ATS) in San Diego, the Pulmonary Vascular Research Institute (PVRI) in Bad Nauheim, Germany, and the 7th International Neonatal and Childhood Pulmonary Vascular Disease Conference in San Francisco. Additionally, Dr. Rabinovitch gave a State of the Art Review at the NIH 1st Annual Drug Discovery and Development Symposium for Pulmonary Hypertension in Bethesda, MD, and gave Research Rounds at NYU’s Langone Medical Center, the University of California, San Diego, the University of Wisconsin-Madison, and at the CVI seminar series of Boston University. At Stanford, Dr. Rabinovitch received the 2015 Department of Pediatrics Mentor Award of Excellence.

The Journey from the Bench to the Bedside: Dr. Rabinovitch and a team from Stanford and Proteo were invited by the FDA to discuss the development plan for Elafin (Tiprelestat) injection for the treatment of pulmonary arterial hypertension. Elafin, an elastase inhibitor, is being developed by Proteo (http://proteo.us/) in collaboration with Marlene Rabinovitch, M.D., at Stanford University. Elafin received Orphan Drug Designation for treatment of PAH by the FDA and in Europe. The team is preparing a Pre-Investigational New Drug Application (PIND) in 2016. Description: mroof HD:Users:michalroof:Desktop:Pre IND Meeting Photos:Elafin PreIND website IMG_1897.JPG

 

 

 

 

 

 

 

 

 

 

 

Pictured, from left:  Drs. Roham Zamanian (Stanford), Michal Roof (Stanford), Juergen Paal (Proteo), Marianne Mann (Consultant), Marlene Rabinovitch, Hanna Ng (Consultant, SRI) and Oliver Wiedow (Proteo), in front of Building 22 in the FDA White Oak Campus, Silver Spring, Maryland, November 4, 2015.

Our Post Doctoral Fellows Presentations:

The lab was once more well-represented at the two key conferences of the cardiovascular field. Three of our fellows presented their research as posters at the 2015 International Conference of the American Thoracic Society (ATS) in Denver, CO, in May. Pin-I Chen, PhD, presented “Amphetamine Enhances the Propensity of Pulmonary Arterial Endothelial Cells to Apoptosis and DNA Damage via pAkt-Dependent Pathways” (P-I Chen, A Cao, NF Tojais, CG Li, L Wang, M Rabinovitch); Jan K Hennigs, MD, presented “The Transcriptional PPARγ-p53 Complex Represses Osteoprotegerin Expression Upon DNA Damage to Inhibit Pulmonary Arterial Smooth Muscle Cell Proliferation” (Jan K. Hennigs, Matthew Roughley, Pin-I Chen, C. Grace Li and Marlene Rabinovitch); and Nancy F Tojais, PhD, presented “Pulmonary arterial hypertension patients with BMPR2 mutation show impaired vascular elastin fiber assembly” (NF Tojais, A Cao, P-I Chen, RK Hopper, CJ Rhodes, L Wang, M Rabinovitch). In November, at the 2015 American Heart Association (AHA) Scientific Sessions in Orlando, FL, post doctoral fellow Kazuya Miyagawa, MD, PhD presented a poster on “Contact-Mediated Interaction between Pulmonary Artery Endothelial and Smooth Muscle Cells Promotes a BMPR2-β-catenin-Notch1 Signal Causing Hyperpolarization of Endothelial Mitochondria and a Stalk Cell-Like Phenotype” (K Miyagawa, CG. Li, JK. Hennigs, S Taylor, JR Moonen, S Sa, L Wang, A Cao, M Rabinovitch).

Lab members also presented their results on work with induced Pluripotent stem cells at the International Society for Stem Cell Research in Stockholm, Sweden, in June 2015. Postdoctoral fellow Mingxia Gu, MD, PhD, presented her work on “Patient-specific IPSC Derived Endothelial Cells Uncover Mechanisms Related to Penetrance of a BMPR2 Mutation in Causing Pulmonary Arterial Hypertension” (M Gu, S Sa, Y Ma, JC Wu, M Rabinovitch) and a poster reported the work of Research Associate Silin Sa, PhD, on “Induced Pluripotent Stem Cell Derived Endothelial Cells as Surrogates for Drug Screening in Idiopathic Pulmonary Arterial Hypertension” (S Sa, A Cao, M Gu, Y Ma, R Fong, CG Li, L Nguyen, JC Wu, M Rabinovitch). In January 2016, postdoctoral fellow Caiyun (Grace) Li, PhD, will present a poster on “PPARgamma controls the DNA damage response by modulating UBR5 interaction with the MRE11-RAD50-NBS1 complex” (CG Li, CS Mahon, E Verschueren, V Kantamani, K Cimprich and M Rabinovitch) at the Keystone Symposium on Nuclear Receptors: Full Throttle in Snowbird, UT.

2014:

Dr. Rabinovitch spoke at the Joint Symposium of the Excellence Cluster Cardio-Pulmonary System (ECCPS), the 2014 International Conference of the American Thoracic Society (ATS) in San Diego, the Pulmonary Vascular Research Institute (PVRI) in Bad Nauheim, Germany, and the 7th International Neonatal and Childhood Pulmonary Vascular Disease Conference in San Francisco. Additionally, Dr. Rabinovitch gave a State of the Art Review at the NIH 1st Annual Drug Discovery and Development Symposium for Pulmonary Hypertension in Bethesda, MD, and gave Research Rounds at NYU’s Langone Medical Center, the University of California, San Diego, the University of Wisconsin-Madison, and at the CVI seminar series of Boston University.

Postdoctoral fellow Rachel Hopper, MD, presented a talk on “HMGA1 may contribute to development of vascular lesions in pulmonary arterial hypertension by promoting endothelial to mesenchymal transition” (Hopper RK, Rhodes CJ, Tojais NF, Rabinovitch M) at the Pulmonary Vascular Research Institute (PVRI) Symposium at Bad Nauheim, Germany in January 2014. Also in January, Caiyun (Grace) Li, PhD, was awarded a travel scholarship by the NIH NIDDK/NIA to present a poster at the Keystone Symposium on Nuclear Receptors in Taos, on “The role of PPARgamma in DNA damage sensing and repair, that is perturbed in pulmonary arterial hypertension.” In the spring, Pin-I Chen, PhD, presented a poster “Amphetamine enhances the susceptibility of pulmonary arterial endothelial cells to apoptosis and DNA damage” (Chen P-I, Cao A, Li CG, Tojais NF, Wang L, Diebold I, Rabinovitch M) at the Keystone Symposium on Metabolism and Angiogenesis in Whistler, British Columbia.

At the 2014 International Conference of the American Thoracic Society (ATS) in San Diego, CA , Post doctoral fellow Nils Nickel, MD presented a mini-symposium talk on “The Human Neutrophil Elastase Inhibitor Elafin Interacts With Caveolin-1 To Facilitate BMPR-2 Signaling And Endothelial Homeostasis Associated With Reversal Of Experimental Pulmonary Hypertension” (Nickel NP, Kaschwich M, Diebold I, Li CG, Spiekerkoetter E, Rabinovitch M). Post doctoral fellow Rachel Hopper, MD, presented a poster on “HMGA1 may contribute to development of vascular lesions in pulmonary arterial hypertension by promoting endothelial to mesenchymal transition.” (Hopper RK, Rhodes CJ, Tojais NF, Rabinovitch M.)

In November, at the 2014 American Heart Association (AHA) Scientific Sessions in Chicago, IL, Caiyun (Grace) Li, PhD, presented a talk on “PPARgamma plays a novel role in DNA damage sensing and repair, that is perturbed on PAH” (Li CG, Sweeney N, Kantamani V, Sa S, Hennigs JK, Diebold I, Rabinovitch M).  Dr. Li won a Stanford Cardiovascular Institute travel award to attend the meeting). Postdoctoral fellow Toshie Saito, MD, presented the poster “Locally produced SAMHD1 immune complexes are associated with the development of idiopathic pulmonary arterial hypertension” (Saito T, Tamosiuniene, Sharpe O, Robinson WH, Nicolls MR, Rabinovitch M), and post doctoral fellow Jan K Hennigs, MD, PhD, presented a poster on “A novel DNA-damage inducible interaction between peroxisome proliferator activated receptor gamma and p53 regulates pulmonary arterial endothelial cell homeostasis” (Hennigs JK, Li CG, Diebold I, Rabinovitch M)

Current Major Grants:

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 (2012) 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 .  An application for five more years of funding was submitted, to understand the molecular signature of Elafin and continue the translation of Elafin to clincal treatment of PAH.

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

Also in 2012, 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

In The Spotlight

Dr. 
Rabinovitch

Marlene Rabinovitch M.D.
Dwight and Vera Dunlevie Professor of Pediatrics
Professor (by courtesy) of Developmental Biology
Staff Scientist, 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

In Pulmonary Arterial Hypertension, Reduced BMPR2 Promotes Endothelial-to-Mesenchymal Transition via HMGA1 and its Target Slug.
Hopper RK, Moonen J-R AJ, Diebold I, Cao A, Rhodes CJ, Tojais NF, Hennigs JK, Gu M, Wang L, Rabinovitch M.
Circulation. Published ahead of print on April 4, 2016.

Accompanying Editorial by Stenmark KR, Frid M, Perros F: Endothelial-to-Mesenchymal Transition: An Evolving Paradigm and a Promising Therapeutic Target in PAH.

RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension.
Rhodes CJ, Im H, Cao A, Hennigs JK, Wang L, Sa S, Chen PI, Nickel NP, Miyagawa K, Hopper RK, Tojais NF, Li CG, Gu M, Spiekerkoetter E, Xian Z, Chen R, Zhao M, Kaschwich M, Del Rosario PA, Bernstein D, Zamanian RT, Wu JC, Snyder MP, Rabinovitch M.
Am J Respir Crit Care Med. 2015 Aug 1; 192(3):356-66.
(PMID: 26030479)

Elafin Reverses Pulmonary Hypertension via Caveolin-1-Dependent Bone Morphogenetic Protein Signaling.
Nickel, N. P., Spiekerkoetter, E., Gu, M., Li, C. G., Li, H., Kaschwich, M., Diebold, I., Hennigs, J. K., Kim, K., Miyagawa, K., Wang, L., Cao, A., Sa, S., Jiang, X., Stockstill, R. W., Nicolls, M. R., Zamanian, R. T., Bland, R. D., Rabinovitch M.
Am J Respir Crit Care Med. 2015; 191 (11) 1273-1286.
(PMID: 25853696)

BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension.
Diebold I, Hennigs JK, Miyagawa K, Li CG, Nickel NP, Kaschwich M, Cao A, Wang L, Reddy S, Chen PI, Nakahira K, Alcazar MA, Hopper RK, Ji L, Feldman BJ, Rabinovitch M. Cell Metab. 2015 Apr 7;21(4):596-608. (PMID: 25863249)

Lung matrix and vascular remodeling in mechanically ventilated elastin haploinsufficient newborn mice.
Hilgendorff A, Parai K, Ertsey R, Navarro E, Jain N, Carandang F, Peterson J, Mokres L, Milla C, Preuss S, Alcazar MA, Khan S, Masumi J, Ferreira-Tojais N, Mujahid S, Starcher B, Rabinovitch M, Bland R.
Am J Physiol Lung Cell Mol Physiol. 2015 Mar 1;308(5):L464-78. 
(PMID: 25539853)

Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension.
Rabinovitch M, Guignabert C, Humbert M, Nicolls MR.
Circ Res. 2014 Jun 20;115(1):165-75.
(PMID: 24951765)

Reduced BMPR2 Expression Induces GM-CSF Translation and Macrophage Recruitment in Humans and Mice to Exacerbate Pulmonary Hypertension. 
Sawada H, Saito T, Nickel NP, Alastalo TP, Glotzbach JP, Chan R, Haghighat L, Fuchs, G, Januszyk M, Cao A, Lai YJ, de Jesus Perez VA, Kim YM, Wang L, Chen PI, Spiekerkoetter E, Mitani Y, Gurtner GC, Sarnow P, Rabinovitch M. Journal of Experimental Medicine 2014 Feb 10;211(2):263-80.
(PubMedID: 24446489)

See SCOPE, Stanford Medicine Blog

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)

Link to all Publications...

Selectd Featured 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.
Editorial: Morty RE, American Journal of Respiratory and Critical Care Medicine Vol 184. pp. 496-497 (2011)

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). de Jesus Perez VA, et al., Journal of Cell Biology 2010; 192 (1): 171-188
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