# The contribution of hypoxia inducible factor-1-dependent glycolysis in lung interstitial macrophages to the pathobiology of schistosomiasis-induced pulmonary hypertension.

> **NIH NIH K08** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $169,020

## Abstract

Project Summary/Abstract
 Schistosomiasis-induced pulmonary hypertension (Sch-PH) is globally the most common cause of
pulmonary arterial hypertension (PAH), and its classification as a “neglected tropical disease” underscores the
large unmet need in understanding the disease pathobiology and developing effective treatments. Although
accumulating data support the likely contribution of the transcription factor hypoxia inducible factor-1 (HIF-1) and
HIF-1-regulated glycolysis to the pathogenesis of PH, their significance in Sch-PH is largely unknown. This
proposal examines the potential role of HIF-1-dependent glycolysis in promoting Sch-PH, specifically in lung
interstitial macrophages (IMs). Available data demonstrate increased pulmonary perivascular infiltration of IMs
in both humans and experimental mice with Sch-PH; increased transcription of HIF-1-associated genes encoding
glycolytic enzymes in murine lung IMs with Sch-PH; and a protective effect of HIF-1α deletion in LsyM+ myeloid
cells against murine Sch-PH. Building upon these key insights, this proposal will test the hypothesis that HIF-1-
dependent glycolysis in perivascular lung IMs critically contributes to the development of Sch-PH. Of the three
potential growth-promoting mechanisms of glycolysis--lactate fermentation, the pentose phosphate pathway,
and the mitochondrial Krebs cycle--the potential mechanistic link between lactate and pulmonary artery smooth
muscle cell (PASMC) proliferation will be additionally examined. Two aims are proposed. Aim 1 will determine
necessity and sufficiency of lung IM HIF-1α stabilization in Sch-PH by conditionally deleting and stabilizing HIF-
1α in IMs of transgenic mice. The effect of lactate dehydrogenase A (LDH-A; an enzyme responsible for lactate
fermentation) deletion and oxamate (LDH-A inhibitor) treatment on Sch-PH severity will be examined. Aim 2 will
spatiotemporally phenotype lung IMs, quantify their glucose metabolism, and test, using co-culture, if lung IM-
derived lactate induces a pro-proliferative, pro-fibrogenic phenotype in PASMCs. Completion of the project will
clarify how glucose metabolism in lung IMs contributes to Sch-PH pathobiology.
 The proposed career development plan was designed with the ultimate goal of supporting the applicant’s
successful transition to independence as a clinician-scientist, in the field of pulmonary vascular metabolism. The
plan leverages the combined expertise of his mentors and advisors in basic-translational research, their
commitment to mentorship, and the collective resources for research and professional development at UCSF. In
the five years of training, the applicant will acquire proficiency in key experimental approaches (spatially resolved
proteomics; flow cytometry and cell sorting; Seahorse metabolic assay; mass spectrometry; and confocal
microscopy), develop data analytical skills, disseminate his findings, and refine grantsmanship, collectively
positioning him as an expert investigator in...

## Key facts

- **NIH application ID:** 10644936
- **Project number:** 1K08HL168310-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Michael Hyunjean Lee
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $169,020
- **Award type:** 1
- **Project period:** 2023-04-05 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10644936

## Citation

> US National Institutes of Health, RePORTER application 10644936, The contribution of hypoxia inducible factor-1-dependent glycolysis in lung interstitial macrophages to the pathobiology of schistosomiasis-induced pulmonary hypertension. (1K08HL168310-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10644936. Licensed CC0.

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