# Exploiting neointimal and vascular smooth muscle cell heterogeneity to reveal mechanisms driving venous neointimal growth and vascular remodeling in pediatric pulmonary hypertension

> **NIH NIH K08** · STANFORD UNIVERSITY · 2024 · $165,996

## Abstract

Abstract
Pediatric Pulmonary hypertension (PPH) is a progressive and incurable disease hallmarked by abnormal
development, muscularization and blockage of small pulmonary vessels by the formation of obstructive
‘neointimal lesions’. While most research has focused on arterial disease, venous changes including neointima,
are described in nearly all forms of PPH but little is known about what controls vein neointima formation. Available
therapies do not target lesion growth, neither prevent nor reverse disease, and are contraindicated when vein
remodeling predominates. Early evidence suggests novel heterogeneity among pulmonary vascular smooth
muscle cells (VSMCs) and neointima, but the molecular control and contribution of these subsets in PPH remains
unknown. Understanding the biology of post-capillary vascular remodeling and, more generally, how
heterogeneous VSMC and neointimal subsets contribute to PPH has the potential to significantly advance the
understanding of the cellular and molecular controls of pathologic vascular remodeling in PPH. In Aim 1, Dr. Lea
Steffes will train with mentors Dr. Maya Kumar in mouse transgenics, cutting-edge imaging and quantitation
techniques and Dr. Mark Krasnow in advanced biocomputational analysis to define transcriptomic heterogeneity
between pre- and post-capillary neointima and provide the first genomic-wide characterization of vein neointima.
In addition to an in vivo pharmacologic inhibition study in mice using tools developed and published by Drs.
Steffes and Kumar, in Aim 2, Dr. Steffes will train with advisor Dr. David Cornfield to perform a broad in vitro
screen of VSMC growth modulators on vein neointima cells. With training in human pulmonary vascular
histopathology from advisors Drs. Serena Tan and Csaba Galambos, Aim 3 will connect Dr. Steffes’s research
and clinical expertise by interrogating the role of two novel developmental VSMC subsets in heritable PPH. The
Candidate Training Plan provides a complimentary skillset of in vitro investigation, bio-computational analysis,
and human lung vascular histopathology training to interrogate the cell-specific behaviors and molecular
signatures of pathologic cell types (vein neointima, Aims 1&2 and developmental VSMC subsets, Aim3) integral
to PPH. Mentor Dr. Maya Kumar is a thought-leader in the use of advanced mouse genetics and genomic tools
to interrogate pathologic pulmonary vascular biology. Co-mentor Dr. Mark Krasnow (single cell analysis) and
advisors Dr. David Cornfield (in vitro analysis) and Dr. Serena Tan (human lung histopathology) and Dr. Csaba
Galambos (pediatric PPH pathology) offer complementary expertise. The environment at Stanford University is
renowned for collaborative and innovative research. Supported by this infrastructure, candidate Dr. Steffes has
demonstrated tremendous academic growth with 9 publications including 5 as first-author since 2020. In
summary, this strong mentoring environment and training plan are anticipated t...

## Key facts

- **NIH application ID:** 10865559
- **Project number:** 1K08HL173632-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Lea Steffes
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $165,996
- **Award type:** 1
- **Project period:** 2024-05-05 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10865559

## Citation

> US National Institutes of Health, RePORTER application 10865559, Exploiting neointimal and vascular smooth muscle cell heterogeneity to reveal mechanisms driving venous neointimal growth and vascular remodeling in pediatric pulmonary hypertension (1K08HL173632-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10865559. Licensed CC0.

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