# Angiotensin Signaling Underlies Myeloid and Sensory Disruption in Diabetes

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $480,845

## Abstract

Project Summary/Abstract
 Neuropathy associated with type 2 diabetes (T2D) is frequently associated with pain and sensory loss. Our
incomplete mechanistic understanding of the pathophysiology of nerve injury in T2D hinders our ability to develop
more effective drugs and therapeutic strategies. Given the emerging role of myeloid cells, particularly
macrophages, across various types of neuropathy, their apparent involvement in diverse forms of nerve injury
pain and the known increase in production of the peptide hormone angiotensin II (Ang II) in diabetes, we posit
that elevated Ang II in T2D precipitates neuropathy, pain and sensory loss by disrupting myeloid cell development
and phenotype. However, many knowledge gaps persist.
 Our preliminary studies indicate that circulating immature myeloid cell numbers are increased in diet-induced
and genetic models of T2D, a change also associated with elevated levels of Ang II in lymphoid tissues.
Furthermore, the sensory gain observed in diet-induced T2D is reversible by inhibitors of Ang II production. The
overall goal of this project is to identify how Ang II disrupts myeloid cells in T2D, culminating in neuropathy,
sensory loss and pain.
 The first specific aim will assess the extent of alterations to myelopoiesis across the progression from
metabolic syndrome to early stage T2D to late-stage T2D, and whether increases in Ang II are causally related.
The second specific aim will determine the degree to which T2D modifies tissue-resident myeloid cell function in
ways that promote sensory dysfunction. Finally, the third specific aim will determine if opposing T2D-related
changes in angiotensin signaling can normalize pathological changes to myeloid cells, thereby reducing sensory
dysfunction.
 Our multidisciplinary approach involves preclinical T2D models, reflexive and voluntary pain-behavioral
studies, immunohistochemistry, in vitro live cell functional imaging, single cell RNA and ATAC-sequencing and
transcriptomic analysis of human skin biopsies. Our project will unambiguously dissect the nature of Ang II-based
myeloid cell disruption to determine the role of the renin-angiotensin system and macrophage-driven
inflammation in the development of peripheral neuropathy and chronic pain in T2D.
 Elucidating the mechanistic underpinnings of sensory loss and pain in T2D neuropathy is critical to advancing
our understanding of the underlying mechanism(s), as well as rapid translation into development of new-
generation, efficacious, non-opioid analgesics that target such neuro-immune crosstalk.

## Key facts

- **NIH application ID:** 10877483
- **Project number:** 1R01DK132019-01A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Andrew John Shepherd
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $480,845
- **Award type:** 1
- **Project period:** 2024-05-02 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877483

## Citation

> US National Institutes of Health, RePORTER application 10877483, Angiotensin Signaling Underlies Myeloid and Sensory Disruption in Diabetes (1R01DK132019-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10877483. Licensed CC0.

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