# Chronic Kidney Disease-Induced Defects Initiated by SIRPα

> **NIH VA I01** · MICHAEL E DEBAKEY VA MEDICAL CENTER · 2024 · —

## Abstract

Chronic kidney disease (CKD) is a major public health problem, afflicting an estimated 15% (37
million) of US adults. Among Veterans, the prevalence of CKD is nearly 50% higher than that of the US
general population. CKD-associated mortality is significantly higher than that of the general population
and worsens with each stage of progressive CKD. The reason for these adverse outcomes is generally
attributed to the development of cardiovascular disease and changes in myocardial size. There are
several critical gaps in our current knowledge of cardiac remodeling in CKD. Our long term goal is to
identify the molecular mechanisms responsible for CKD-induced cardiomyopathy.
 We have previously identified that signal regulatory protein alpha (SIRPα) is upregulated as a
mediator of CKD-induced insulin resistance in skeletal muscles. Specifically, that CKD stimulates
inflammation to upregulate SIRPα in skeletal muscles of mice and patients with CKD. Subsequently,
SIRPα promotes insulin resistance in skeletal muscles and adipose tissue causing cachexia. CKD
stimulates the opposite responses in the heart with increases in myocardial mass. The significance of
our proposal is that we provide evidence for a differential role of SIRPα in mediating cachexia in skeletal
muscles and adipose tissues while contributing to the development of increased cardiac muscle growth.
We predict cardiac remodeling in CKD may be the result of impairments in myocardial insulin/insulin
growth factor-1 (IGF1) receptor signaling.
 CENTRAL HYPOTHESIS: SIRPα behaves as a novel myokine impairing myocardial
insulin/IGF1 receptor functions while promoting CKD-induced cardiomyopathy. Guided by strong
preliminary data we propose three Specific Aims to characterize the metabolic milieu of CKD and its
effects on myocardial mass: (1) Determine if SIRPα exacerbates myocardial insulin/IGF1 receptor
signaling in CKD. (2) Identify CKD-specific (i.e. uremia) triggers that cause SIRPα release. (3) Evaluate
the anti-proteolytic effects of SIRPα in modulating myocardial protein turnover in CKD.
 Our goal is to determine if SIRPα interacts with insulin/IGF1 receptor impairing intracellular
signaling to promote myocardial growth and cardiac dysfunction. This discovery will stimulate novel
targets for therapies to prevent CKD-associated heart failure and potentially improve the lives of
Veterans suffering from its deleterious consequences.

## Key facts

- **NIH application ID:** 10867302
- **Project number:** 5I01BX005792-02
- **Recipient organization:** MICHAEL E DEBAKEY VA MEDICAL CENTER
- **Principal Investigator:** Sandhya S Thomas
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867302

## Citation

> US National Institutes of Health, RePORTER application 10867302, Chronic Kidney Disease-Induced Defects Initiated by SIRPα (5I01BX005792-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10867302. Licensed CC0.

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