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Postdoctoral Training

Postdoctoral opportunities are available for young scientists interested in pursuing research in pulmonary vascular disease. We pride ourselves on developing outstanding scientists who are positioned to become the next generation of thoughtful leaders in pulmonary vascular disease.

 

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We offer Summer Internships for graduate, undergraduate and high school students interested in a career in medicine or science. The goals of our program include increasing interest in biological sciences and medicine, helping students to understand how scientific research is performed, and increasing diversity of students and researchers in the sciences.

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Our Research Funding

Dr. Rabinovitch supported by the Dwight and Vera Dunlevie endowed Professorship. Our research funding includes grants from the National Institutes of Health, and from research foundations in the USA and abroad. More 

NIH Funding:

Pulmonary Hypertension in Genetically Modified Mice (NIH/NHLBI grant R01 HL074186)
Funding period: 04/01/04 – 01/31/24
Principal Investigator: Marlene Rabinovitch
Collaborators: Mark R Nicolls and Michael P Snyder
This is the fourth period of this grant. The application builds upon our recent studies indicating that aldehyde dehydrogenase (ALDH) enzymes can be critical metabolic switches that link chromatin remodeling with gene expression in vascular and inflammatory cells, and that the dysregulation of specific ALDH isoforms is linked in the pathogenesis of pulmonary arterial hypertension (PAH). We use pulmonary arterial (PA) endothelial cells (EC), smooth muscle cells (SMC) and macrophages (MØ) and genetically modified mice to pursue our novel observations. Aim 1 probes the mechanism by which elevated ALDH1A3 increases cell cycle genes and other metabolic enzymes and study the impact of those enzymes on chromatin remodeling and gene expression. Aim 2 will determine whether ALDH3A1 protects PA EC under laminar flow and ALDH2 under static conditions by relating their metabolomic profile to chromatin accessibility and gene expression. In Aim 3 we focus on ALDH1A2, an ALDH isoform implicated in polarization of MØ associated with resolution of inflammation, similar to the reported effect of BMPR2 ligands. We will determine whether deleting Aldh1a2 or Bmpr2 in interstitial MØ recruited to the lung in association with PH producing conditions, causes more severe disease related to persistent perivascular inflammation, apply proteomics to analyze the secretome of these Aldh1a2 or Bmpr2 deleted MØ to better define the nature of the inflammatory response, and investigate the impact of the MØ with Aldh1a2 or Bmpr2 deleted on EC apoptosis or endothelial mesenchymal transition.

The BMP-PPARgamma Axis and Pulmonary Hypertension (NIH/NHLBI grant R01 HL087118)
Funding period: 12/01/06 – 12/31/19 (pending renewal, to 03/31/24)
Principal Investigator: Marlene Rabinovitch
Collaborator: Michael P Snyder
We build upon our observation that In PAH PAEC, high IL6 levels are directly related to the phosphorylation of PPARγ and its impaired interaction with MRN and UBR5, causing elevated ATMIN and impaired DNA damage sensing via phosphoATM. Aim 1 will determine whether high endogenous IL6 levels phosphorylate PPARγ by activating CDK5, whether phosphorylation of PPARγ disrupts its interaction with UBR5 and MRN, and if this is a function of loss of BMPR2, the gene mutant in familial PAH and reduced in idiopathic (I) PAH. We also investigate whether sites of unrepaired DNA damage are associated with specific changes in chromatin accessibility and gene regulation that impact cell phenotype and whether reversal of DNA damage in PAH PAEC restores chromatin accessibility and gene regulation. In Aim 2 will use two murine models to study the role of DNA damage in the pathogenesis of pulmonary hypertension (PH). Aim 3 pursues the DNA damage associated with phosphoPPARγ in PAH monocytes and determine whether this is a feature of loss of BMPR2 that is associated with a highly pro-inflammatory pattern of gene expression that can be reversed by roscovitine, the CDK5 inhibitor. These studies should provide a major inroad into understanding the molecular and functional sequelae of unrepaired DNA in vascular disease and their potential for reversibility of disease.

Integrative Omics as a Discovery Tool for Pulmonary Hypertension (NIH/NHLBI grant R01 HL122887)
Funding period: 08/01/15 – 05/31/19
Principal Investigators: Marlene Rabinovitch, Mark R Nicolls and Michael P Snyder
Collaborator: Purvesh Khatri
This project develops and applies innovative bioinformatics methods of analysis to integrate very large publicly available data sets with novel data sets derived from state-of-the-art transcriptomic and metabolomic technologies, to generate a powerful systems biology approach to characterize pulmonary arterial hypertension (PAH). Aim 1 applies big-data analysis techniques to publicly available PAH data sets to develop a common PAH module. Aim 2 will generate the transcriptomes (by RNA-seq) and the metabolomes (by mass spectrometry) of vascular cells (EC, SMC and fibroblasts), and inflammatory cells (T cells, B cells and macrophages) isolated from explanted human PAH lungs and from control lungs. The data sets generated will be used to find common aberrant pathways in different vascular and inflammatory cells that could be targeted therapeutically in PAH. Companion studies in rodents will focus on the relationship of the pathways identified to the evolution of PAH. Aim 3 combines data from Aims 1 and 2 and extends our topology-based impact factor pathway analysis method to account for interactions between metabolites and genes, as well as between pathways, emergent dominant processes prioritized for hypothesis testing, and animal models approximating these PAH pathways developed to test relevance to human PAH. These models, as well as cultured cells from patients with PAH, will be used to explore therapies, beginning with those that repress critical pathways.

Endothelial Injury, BMPR2 Dysfunction and Macrophage Activation Cause EndMT and PAH (NIH/NHLBI grant R01 HL138473)
Funding period: 07/01/17 – 06/30/21
Principal Investigators: Marlene Rabinovitch and Mark R Nicolls
Collaborator: Maria Ariza, The Ohio State University
This project addresses the hypothesis that injured pulmonary arterial endothelial cells (PAECs) with dysfunctional bone morphogenetic receptor (BMPR2) signaling recruit and activate macrophages (MØs) that amplify leukotriene (LTB4) and the endogenous retrovirus HERV-K; we further hypothesize that these immune factors work in concert to sustain inflammation and promote severe pulmonary arterial hypertension (PAH) by inducing endothelial cell (EC) apoptosis and endothelial to mesenchymal transition (EndMT). Aim 1 evaluates how LTB4 may be autonomously produced by injured PAECs, which in turn activate MØs to stimulate further LTB4 biosynthesis to cause PAEC apoptosis and EndMT when BMPR2 signaling is impaired. Aim 2 evaluates whether PAECs from PAH patients including those with reduced BMPR2 function, secrete factors in response to oxidant or inflammatory injury, that amplify HERV-K expression in monocytes. Aim 3 investigates the vulnerability of BMPR2-deficient animals to develop severe pulmonary hypertension and EndMT using a mouse with loss of BMPR2 in fate mapped EC, and a new transgenic rat PH model with BMPR2 haploinsufficiency. The animals are treated with endotracheal instillation of Ad-5LO to generate high LTB4 levels or recombinant HERV-K dUTPase given intravenously.

Elafin Therapy for Pulmonary Arterial Hypertension (NIH/NHLBI Grant P01 HL108797)
Funding Period: 08/17/11 – 06/30/22
Principal Investigator: Marlene Rabinovitch
Clinical Project PI: Roham T Zamanian, MD
Advanced Proteomics Phenotyping Core: Garry P Nolan, PhD and Wendy Fantl, MD
This is a competitive renewal of our Program Project “Elafin Therapy for Lung Diseases”. Our Cycle II translational Program Project grant (tPPG) builds on the success of Cycle I, focusing on PAH. The goal of Project 1 is to better understand why and in whom Elafin is most likely to show clinical efficacy, investigating the role of Elafin in neutrophil function and interaction with pulmonary arterial endothelial cells (PAEC). EC derived from induced pluripotent stem cells will be investigated as surrogates for native PAEC to understand responsivity to Elafin, and will define the interactome of Elafin to identify novel functions and potential pitfalls of this therapy. In the Advanced Proteomic Phenotyping Core, we will use CyTOF to extend the ‘PAH signature’ we have found in PBMCs and investigate the extent to which this abnormal signature is modified by Elafin both in vitro and in subjects being treated with Elafin. We will use MIBI and apply ABseq to determine the biology of immune cells and neutrophils that are recruited to the lung perivascular niche. The Clinical Project includes a Phase I clinical trial with pharmacokinetic and toxicity endpoints, a 180 day GLP toxicity and pharmacokinetic study in the rat and a small multi-center Phase II clinical trial in patients, with toxicity, pharmacokinetic and efficacy endpoints.

Pulmonary Hypertension Breakthrough Initiative - Stanford Transplant Preparation Center (NIH/NHLBI Grant R24 HL123767)
Funding period: 09/15/14 – 06/30/19
Principal Investigator: Mark Geraci, Indiana University, Indianapolis, IN (Prime: NIH/NHLBI)
Stanford Principal Investigator: Marlene Rabinovitch
Stanford Center co-Director: Roham Zamanian, MD
This project is to leverage the resources and unique expertise developed by the Pulmonary Hypertension Breakthrough Initiative (PHBI) Network under funding by the AHA-CMREF, into an NIH-supported initiative to accrue specimens of disease-specific groups, which will be highly integrated with pathologic, genetic, and genomic sub-phenotypes pertaining to lung and blood specimens, and expanding to the failing pulmonary arterial hypertension (PAH) heart. Since its establishment in 2006, the PHBI successfully developed a novel and unique infrastructure, whose success relied on the active participation of a highly integrated network of university-based sites with extensive expertise in each of the spheres of competency: excellence in clinical care of PAH (including patient accruals), lung transplantation, pathology, genetics, genomics, and cell isolation. The Stanford Transplant Preparation Center is charged with the harvest and preparation of the explanted lung and heart for processing in accordance with the Network’s protocols, in such a manner that it will be useful to investigators of the PHBI Network for the broadest spectrum of studies.

Research Training Award:
Stanford Career Development Program in the Omics of Lung Diseases (NIH/NHLBI grant K12 HL120001)
Funding period: 09/01/13 – 05/31/19
Principal Investigators: Marlene Rabinovitch, Mark R Nicolls, Michael P Snyder
This is a Career Development Program (CDP) in ‘Omics’ of lung diseases with a major focus on pulmonary arterial hypertension (PAH). This is an extension of the successful Stanford K12 CDP on the “Genetics and Genomics of Lung Diseases” that focuses on PAH. The new CDP proposal allows us to equip the next cadre of MD and PhD scientists with interdisciplinary and bioinformatic skills to integrate new high throughput genomic, proteomic and metabolomic platforms to gain a better understanding of disease pathophysiology.


Recently completed NIH-funded project:

iPSC Derived EC as Surrogates Using Pulmonary Hypertension as a Prototype Disease (NIH/NHLBI grant U01 HL107393)
Funding period: 07/05/11 – 06/30/17
Principal Investigators: Marlene Rabinovitch, Michael P Snyder, Joseph C Wu
This project compared native pulmonary arterial PAECs from idiopathic pulmonary hypertensive (PAH) vs. control lungs to ECs transformed from induced pluripotent stem cells (iPSCs) that were derived from skin fibroblasts. We investigated gene variants by Exome and whole genome sequencing, DNA methylation by Methyl-Seq and RNA expression by RNA-Seq. We then related these data to cell phenotype as assessed by angiogenesis assays. This study showed the efficacy of fibroblast-iPSC-ECs as surrogates for native pulmonary arterial endothelial cells (PAEC) in that they showed similar abnormalities when derived from patients with PAH. We then used the fibroblast iPSC-ECs to study correction of function by gene therapy or pharmaceutical agents identified by high throughput screening. They were also used to study the mechanism protecting subjects that were carriers of the BMPR2 mutation from developing PAH.

 


Other Funding for Current Research Projects

Our post doctoral fellows and visiting professors are supported by various agencies, with supplemental funding from the respective NIH/NHLBI grants above.

Mingxia Gu, MD, PhD, is supported by NIH/NHLBI grant K99 HL135258, “Uncovering compensatory mechanisms in family members with disease causing mutations of pulmonary hypertension”. Previous support was by an AHA fellowship.

Sarasa Isobe, MD, PhD is supported by the MSD Life Science Foundation, Public Interest Incorporated Foundation Fellowship Program.

Dan Li, PhD is funded by an American Lung Association (ALA) Senior Research Training Fellowship (grant RT-509274).

David Marciano, PhD, is funded by an NIH/NHLBI Individual NRSA post-doctoral fellowship (grant F32 HL132452).

Marcy Martin, PhD, is funded by NIH/NHLBI Training grant T32 HL098049 “Stanford Training Program in Mechanisms and Innovation in Vascular Disease”.

Jan-Renier (JR) A J Moonen, MD, PhD is funded by a fellowship from the Tobacco-Related Disease Research Program (TRDRP). He was previously funded by The Netherlands Heart Foundation Grant 2013T116

Tsutomu Shinohara, MD, PhD is supported by the Japan Heart Foundation.

Shoichiro Otsuki, MD, PhD was supported by the department of Pediatrics of Mie University School of Medicine and the Japanese Society of Pediatric Cardiology and Cardiac Surgery.

Shalina Taylor, PhD, is funded by NIH/NHLBI Training grant T32 HL129970 “Stanford Training Program in Lung Biology”.


Funding for our Summer Interns is provided by various sources, including the Stanford Institutes for Summer Research (SIMR), the American Heart Association (AHA), the NIH/NHLBI, and the students’ undergraduate institutions (eg, in the past few years, Claremont McKenna College, Whitman College, SURF program at UC San Diego)

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