Pulmonary arterial hypertension susceptibility in systemic sclerosis patients with the DNASE1L3 R206C variant

The National Institute of Arthritis and Musculoskeletal and Skin Diseases awarded the University of Texas Health Science Center at Houston $156,000 on July 1, 2026, under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846).

The project investigates pulmonary arterial hypertension susceptibility in systemic sclerosis patients carrying the DNASE1L3 R206C genetic variant. Aim 1 will assess the impact of chronic DNASE1L3 deficiency on the pulmonary vasculature in mice by comparing DNASE1L3-null mice to matched wildtype controls for susceptibility to pulmonary arteriopathy and PAH development, both spontaneously with age and when challenged with Sugen 5416/hypoxia exposure. Aim 2 will identify potential circulating mediators of pulmonary arteriopathy in SSC patients with the R206C variant through proteomics screening of serum samples and will evaluate the functional impact of circulating factors on pulmonary arterial endothelial cell apoptosis, proliferation, immune cell adhesion, and gene expression.

Performance occurs in Houston, Texas. The period of performance runs from July 1, 2026, through June 30, 2028. The award is structured as a Project Grant, an assistance type used to support discrete, time-limited research projects within the NIH grant portfolio.

Abstract

Systemic sclerosis (SSC) is a multi-system disease with the highest mortality among major rheumatologic diseases. Though certain genetic loci have been robustly linked to SSC susceptibility, development of effective therapies for SSC is hampered by fragmented understanding of mechanisms by which the identified genetic variants lead to SSC and its end-organ complications. The current proposal is focused on an SSC-susceptibility variant in the coding region of deoxyribonuclease 1-like 3 (DNASE1L3) that results in ARG to CYS substitution at amino acid 206 (R206C). DNASE1L3 loss-of-function causes autoimmunity and predisposes to several autoimmune rheumatic diseases including SSC. The variant encoding DNASE1L3 R206C results in incomplete digestion of circulating self-DNA derived from apoptotic cells, which may underlie the aberrant immune system activity observed in the setting of chronic DNASE1L3 loss-of-function. This proposal is designed to determine the impact of DNASE1L3 loss of function on susceptibility to pulmonary arterial hypertension (PAH), which is the second leading cause of SSC-related mortality. Aim 1 of the proposal will determine the impact of chronic DNASE1L3 deficiency on the pulmonary vasculature in mice, by assessing DNASE1L3-null in comparison to matched wildtype mice for susceptibility to pulmonary arteriopathy and PAH development spontaneously with age or when challenged with exposure to sugen 5416/hypoxia. Aim 2 will identify potential circulating mediators of pulmonary arteriopathy in SSC patients with DNASE1L3 R206C via proteomics screen of serum samples. Additionally, the functional impact of circulating factors in SSC patients with DNASE1L3 R206C on pulmonary arterial endothelial cells (paec's), specifically their impact on paec apoptosis, proliferation, immune cell adhesion, and gene expression, will be determined. Together, these studies can establish experimental models for future research on PAH susceptibility in SSC and the potential role of DNASE1L3 loss-of-function in PAH pathogenesis. Elucidating the impact of DNASE1L3 loss- of-function on pulmonary vasculature will provide a foundation for development of targeted therapies for SSC- PAH, which is an unmet need for this lethal SSC complication. The PI is an MD/PHD-trained rheumatologist focused on SSC clinical care and research on the pathogenesis underlying SSC. The PI is currently supported by a K08 career development award. This R03 award will expand the scope of the PI's research and lay the groundwork for a larger proposal focused on elucidating the causal chain from DNASE1L3 loss-of-function to SSC-PAH.