# Insulin Receptor Substrate Signaling in Pulmonary Hypertension

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $386,250

## Abstract

ABSTRACT
 Pulmonary hypertension (PH) is characterized by pulmonary vasculature remodeling and elevated
pulmonary artery pressure that leads to progressive right-sided heart failure and death. Growing evidence
indicates that genetic susceptibility, inflammation, and metabolic shifts in the pulmonary vasculature play key
roles in PH pathogenesis. The mechanisms that underlie PH remain enigmatic because of its tremendous
complexity. Consequently, current therapy for PH is limited primarily to vasodilation. In this application, we
target one of the more proximal signaling hubs in the pathogenesis of PH—insulin receptor substrate 2 (IRS2),
a critical molecule in insulin resistance and cellular energy homeostasis. Because IRS2 is the main regulator of
insulin and insulin growth factor signaling, loss of IRS2 expression promotes insulin resistance and type II
diabetes. Indeed, the loss of IRS2 appears to be deleterious in multiple cell types and disease conditions.
Although the role of IRS2 in insulin signaling has been studied, very little is known about its contribution to
cardiopulmonary pathophysiology, including that seen in PH. Our preliminary data show that IRS2 expression
is decreased in hematopoietic cells of patients with pulmonary arterial hypertension and that IRS2 deletion
exacerbates macrophage activation to pro-PH phenotype, and perivascular muscularization in a mouse model
of PH. Based on our data and other published results, we hypothesize that IRS2 possesses anti-inflammatory
and anti-hyper-proliferative activity in the pathogenesis of PH, and that loss of IRS2 in bone marrow-derived
cells enhances vascular inflammation and promotes a hyper-proliferative microenvironment. Hence, IRS2
might be valuable as a novel biomarker for PH, and restoring IRS2 expression and function might represent a
novel therapeutic target for multifactorial PH pathophysiology. Specific Aim 1 will investigate the correlation
between IRS2 expression in lymphoid cells and the clinical characteristics of patients with pulmonary arterial
hypertension. Specific Aim 2 will determine the anti-inflammatory role of macrophage-derived IRS2 in
pulmonary vascular remodeling and PH development and examine whether IRS2 influences macrophage
activation to a pro-PH phenotype. Specific Aim 3 will test the hypothesis that IRS2 and 5' adenosine
monophosphate-activated protein kinase (AMPK) signaling integrate several key pathways implicated in
pulmonary artery smooth muscle cell proliferation and that restoring IRS2 by adenoviral gene therapy will
reverse experimental PH. The goal of this proposal is to unravel the unrecognized protective role of IRS2—
specifically its ability to suppress inflammation and hyper-proliferative activity during PH development. Thus,
the data generated will support the development of new agents that target multiple downstream inflammatory,
neoplastic, and metabolic mediators of this pathway that can be used for treatment of right heart failure and
PH...

## Key facts

- **NIH application ID:** 10089467
- **Project number:** 5R01HL135022-05
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Achsah D. Keegan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $386,250
- **Award type:** 5
- **Project period:** 2017-12-07 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10089467

## Citation

> US National Institutes of Health, RePORTER application 10089467, Insulin Receptor Substrate Signaling in Pulmonary Hypertension (5R01HL135022-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10089467. Licensed CC0.

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