# The role of sciatic nerve inflammation in diabetic neuropathy

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2022 · $40,496

## Abstract

Abstract
Diabetic neuropathy (DN) is characterized by the retraction of sensory axon terminals in the periphery from their
targets with a “glove and stocking” pattern. The mechanisms of DN remain though, unclear, impairing successful
therapeutic interventions. Unlike type 1 diabetes, type 2 diabetes is accompanied by a systemic metabolic
dysfunction that may contribute to the development of DN. Many patients develop neuropathy while pre-diabetic
and hyperlipidemia, hyperglycemia, and insulin resistance all impair membrane integrity, axon growth, and
mitochondrial motility in sensory neurons. Another important hallmark of the metabolic syndrome is systemic
low-grade inflammation involving inflammatory macrophages. Macrophages are major players in Wallerian
degeneration and have roles in debris clearance as well as recovery from sciatic nerve injury and regeneration.
Whether macrophages in the sciatic nerve contribute or react to diabetic neuropathy is unexplored.
I find in preliminary data that pre-diabetic mice exhibit heat hyposensitivity and decreased skin innervation,
especially for CGRP+ fibers. I also find that pre-diabetic mice have an increased sciatic nerve inflammation
reminiscent of the immediate response to sciatic nerve injury including, CCL2 upregulation and CD68 increase
in macrophages.
Here, I propose to study if and how sciatic nerve macrophages contribute to diabetic neuropathy or react o axon
degeneration. I hypothesize that SCN macrophages contribute to the pathogenesis of type 2 diabetic
neuropathy. In the first aim, I will determine whether CCL2-driven recruitment of macrophages to the nerve
contributes to the onset of heat hyposensitivity. In the second aim, I will determine whether the sustained
increase in CD68+ macrophages/CCL2 signaling in the sciatic nerve contributes to the sustained denervation of
the skin of pre-diabetic mice and whether the denervation can be rescued by CCR2 blockade. Finally, I will
determine whether small unmyelinated c-fibers undergo injury transcriptional reprogramming and to what extent
low-grade inflammation contributes to the DRG neuron transcriptional changes.
This study will improve our understanding of if and how the immune system is involved in the development of
peripheral neuropathies, which remains largely unknown. In addition, this study will also determine how similar
diabetic neuropathy is to sciatic nerve injury models in terms of transcriptional reprogramming. The proposed
work could open new therapeutic avenues for pre-diabetic neuropathy, a significant clinical challenge that is only
increasing, and will improve our knowledge of how sensory neurons respond to metabolic dysfunction.

## Key facts

- **NIH application ID:** 10455226
- **Project number:** 1F31NS127357-01
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Sara Hakim
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $40,496
- **Award type:** 1
- **Project period:** 2022-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10455226

## Citation

> US National Institutes of Health, RePORTER application 10455226, The role of sciatic nerve inflammation in diabetic neuropathy (1F31NS127357-01). Retrieved via AI Analytics 2026-05-31 from https://api.ai-analytics.org/grant/nih/10455226. Licensed CC0.

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