Investigating the function of chitinase 3-like-1 in the pathogenesis of pulmonary arterial hypertension

The National Heart, Lung, and Blood Institute awarded Brown University $100,228 on December 1, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate the role of chitinase 3-like-1 in pulmonary arterial hypertension pathogenesis. The project grant funds research into how the protein CHI3L1 contributes to immune and metabolic dysfunction underlying vascular remodeling in PAH, with particular focus on macrophage metabolism and pro-remodeling effects. The research will interrogate CHI3L1's function in the immune and metabolic processes driving PAH progression, leveraging preliminary findings that CHI3L1 levels are elevated in pulmonary hypertension models and associated with worse hemodynamics in patient populations. Performance occurs in Providence, Rhode Island, with a completion date of May 31, 2028.

Abstract

Pulmonary arterial hypertension (PAH) is a vasculopathy with no cure. Current medications for PAH delay disease progression by acting as pulmonary vasodilators; however, they are incapable of arresting or reversing the pulmonary vascular lesions that occur in this disease. Over the years, evidence of perivascular inflammation and metabolic dysfunction has been documented in PAH, but we have a limited understanding of how they contribute to vascular remodeling responses in this disease. Therefore, this research proposal seeks to elucidate the immune and metabolic dependent processes that occur in PAH specifically in relationship to the non-enzymatic protein chitinase 3-like-1 (CHI3L1). This moiety is the prototypic glycoprotein of the glycosyl hydrolase gene family and has been shown to mediate inflammation, injury, and tissue remodeling responses in various inflammatory conditions and vasculopathies. Our previous studies demonstrated that CHI3L1 levels are elevated in mouse models of pulmonary hypertension (PH) and that high levels of CHI3L1 are associated with worse hemodynamics in PH patients. Taking from the studies highlighting perivascular inflammation and metabolic dysfunction as hallmarks of PAH development, we sought to determine the role of CHI3L1 in these processes. Preliminary studies in our lab demonstrated that macrophages produce CHI3L1 abundantly and we also showed that CHI3L1 knockout and CHI3L1 transgenic mice have different metabolic profile signatures. At present, the question of what is CHI3L1's function during vascular remodeling responses in PAH has not yet been investigated. As such, this research proposal will interrogate the role of CHI3L1 in macrophage metabolism and vascular remodeling. I hypothesize that CHI3L1 impairs metabolism in macrophages and facilitates macrophage pro-remodeling effects in PAH. In aim 1, i will explore the relationship between CHI3L1 and impaired metabolism in lung macrophages by a) identifying how CHI3L1 expression affects the bioenergetic profiles of bone-marrow-derived macrophages isolated from mice, and b) determining whether CHI3L1 influences dysregulated metabolism in primary lung alveolar and interstitial macrophages. In aim 2, i will a) determine the role of macrophage-specific CHI3L1 in endothelial-mesenchymal transition in vitro and how modulating CHI3L1 expression in macrophages affects vascular remodeling in vivo and b) evaluate the therapeutic effects of a CHI3L1 neutralizing antibody delivered to sugen/hypoxia-treated mice via a nanoparticle-based delivery system. The proposed research will be supported by DR. Yang zhou with the CO-sponsorship of DR. Alan morrison. Additional support will be provided by DR. Hongwei YAO, DR. Olin liang, and DR. Jyothi menon, for the execution of the metabolism, vascular remodeling, and therapeutics studies, respectively. The PI will acquire robust research skills in animal studies, immunology, metabolism, and therapeutics while gaining a fundamental understanding of how dysregulated immunity and metabolism lead to pathogenesis.