# Ubiquitination and Endothelial Fibrosis in Early Pulmonary Arterial Hypertension

> **NIH NIH K08** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $168,696

## Abstract

PROJECT SUMMARY/ABSTRACT
 This K08 Mentored Clinical Scientist Research Career Development Award describes a five-year
research and training program to establish the principal investigator (PI) as an independent, R01-funded
physician-scientist in the field of pulmonary vascular medicine. Co-mentorship by Bradley Maron, M.D., an
expert in cysteinyl thiol biochemistry, vascular fibrosis, and PAH pathobiology and pathophysiology, and Joseph
Loscalzo, M.D., Ph.D., an expert in redox biochemistry, network medicine, and proteomics, will oversee the PI’s
research and professional development activities at Brigham and Women’s Hospital and Harvard Medical
School. Scientific publication, guidance from an advisory committee, didactic education, and presentation at
scientific conferences will support the scientific aims of the project and provide career development in three key
training areas: the pathobiology of PAH inception, kinase ubiquitination, and experimental PAH models. The PI
is guaranteed >80% protected academic time to dedicate to the proposed K08 program.
 PAH is characterized by endothelial dysfunction and oxidant stress that promotes fibrotic remodeling of
the pulmonary arterioles, leading to right heart failure, and death. Mortality and hospitalization increase
incrementally beginning at a mean pulmonary artery pressure (mPAP) below values that were previously thought
to be pathogenic. Therefore, treatment of early-stage PAH may improve clinical outcome, but effective therapies
do not exist because the pathobiology of endothelial dysfunction and vascular remodeling in early PAH is not
known. We provide novel data that early-stage PAH is characterized by pulmonary arteriolar fibrosis, impaired
right ventricle-pulmonary artery (RV-PA) coupling, and increased endothelial C-terminal src kinase (Csk)
expression occurring prior to the development of elevated mPAP in vivo. Computational modeling predicts that
the Csk binding-partner and E3 ubiquitin ligase Casitas b-lineage proto-oncogene (Cbl) is susceptible to
oxidative modification at cysteinyl thiol 396 (Cys396). We hypothesize that oxidation of endothelial Cbl-Cys396
prevents Csk ubiquitination to increase Csk-dependent fibrosis and impair RV-PA coupling in early-stage PAH.
To test this hypothesis, we propose the following specific aims: 1) Determine the impact of Cbl-Cys396 oxidation
on Csk ubiquitination and expression in cultured human PAECs, 2) Assess the role of increased endothelial Csk
on fibrillar collagen expression in cultured human PAECs, and 3) Test the effect of Csk inhibition on RV-PA
coupling in early- and advanced-stage PAH in vivo. We anticipate that findings from this K08 will establish Csk-
targeted therapy as a novel strategy by which to prevent or reverse endothelial fibrosis and vascular remodeling
prior to the development of elevated mPAP and right heart failure in PAH. Furthermore, this research program
will establish kinase-ubiquitin ligase dysregulation in early-stage ...

## Key facts

- **NIH application ID:** 9952812
- **Project number:** 1K08HL151976-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Bradley Wertheim
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $168,696
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952812

## Citation

> US National Institutes of Health, RePORTER application 9952812, Ubiquitination and Endothelial Fibrosis in Early Pulmonary Arterial Hypertension (1K08HL151976-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9952812. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*