# Myeloid lineage targeting to improve recovery from injury and surgery: Cellular and molecular mechanisms

> **NIH NIH R35** · STANFORD UNIVERSITY · 2021 · $401,939

## Abstract

Project Summary
Despite the number of people affected each year by persistent pain and poorly healed fractures after nonfatal
traumatic and surgical injury it remains unclear what are the key components of the profound multicellular
response to injury and how they can be manipulated to improve outcomes. In particular, peripheral injury
mobilizes the immune system to resolve tissue damage, however, sustained immune activation can be
detrimental and contribute to delayed healing. Myeloid-lineage cells are instrumental in the innate immune
response to injury- peripherally, as macrophages, and centrally, as yolk sac-derived microglia. Nevertheless, the
temporal and compartment-specific contributions of myeloid-lineage cells to bone healing, perioperative pain
and surgical recovery have yet to be elucidated. Precise manipulation of these myeloid-lineage cells to establish
causation is not possible in humans. To identify cellular and molecular targets for improving recovery we will
therefore take advantage of a clinically informed mouse model of orthopaedic injury. Our central hypothesis is
that there is a critical period during which myeloid-lineage cell involvement is crucial for proper recovery from
injury; however, prolonged activation, marked by cytokine release and loss of homeostatic functions, can
contribute to pain and impaired bone healing ultimately increasing the risk for long-term disability. To pursue this
fundamental work, we will use a combination of molecular and whole organism approaches in which we have
significant expertise including mouse models of complex orthopaedic trauma, affective-motivational readouts of
persistent pain and functional impairment, specific transgenic manipulations and longitudinal imaging of bone
and CNS tissues. In particular, this convergence of capabilities uniquely positions us to answer the following key
knowledge gaps: 1) The innate immune response is instrumental to recovery, but can its dysfunction be
monitored in vivo to identify at risk individuals? 2) What specific molecular signatures of activated myeloid-
lineage cells can be targeted peripherally and centrally to improve outcomes? 3) Is the myeloid-lineage response
to peripheral injury evolutionarily conserved and therefore translationally relevant? The proposed research builds
on our previous work in a mouse model of chronic pain in which we showed that: 1) Myeloid-targeted positron
emission tomography ligands can track dysfunctional innate immune activation, 2) Attenuation of macrophage
and microglial activation can improve persistent pain, 3) New markers can be used to distinguish infiltrating
macrophages from resident microglia in the spinal cord thus clarifying their unique contributions. Ultimately,
these studies will establish how myeloid-lineage cells may be the initial cellular link between peripheral injury,
poor bone healing and severe acute pain. Successful completion of the proposed studies will enhance our
understanding of compartme...

## Key facts

- **NIH application ID:** 10260508
- **Project number:** 5R35GM137906-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Vivianne L Tawfik
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $401,939
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10260508

## Citation

> US National Institutes of Health, RePORTER application 10260508, Myeloid lineage targeting to improve recovery from injury and surgery: Cellular and molecular mechanisms (5R35GM137906-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10260508. Licensed CC0.

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