# Myeloid lineage activation and reprogramming in metabolic dysfunction

> **NIH NIH K01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $92,258

## Abstract

PROJECT SUMMARY
The high prevalence and health impact of obesity drives a critical need to understand the link between obesity
and disease. Monocyte and macrophage activation that contributes to low grade inflammation is one such link.
These myeloid cells contribute to inflammation by producing proinflammatory cytokines, activating other
immune cells, and monocytes can also differentiate into proinflammatory macrophages, all of which are
associated with insulin resistance. However, the mechanisms underlying myeloid cell proinflammatory
activation in human obesity and diabetes are not resolved. My preliminary data identify lysosomal dysfunction
in SRhi myeloid cells as high priority targets for investigation in diabetes. Furthermore, strategies to alleviate
inflammation in metabolic disease have been ineffective, partly due to low cellular specificity. We identify
polymer nanoparticles (NPs) as excellent candidates for a more specific approach. My preliminary data show
increased NP-monocyte interactions in obese diabetic patients vs. non-diabetic, making NPs a promising
approach for targeting myeloid cells in diabetes. My central hypothesis is that obesity disrupts SRhi myeloid cell
lysosomal processing, increasing production of inflammatory mediators, and that NPs can modulate SRhi
myeloid cell inflammatory activation. To examine this hypothesis, I will use monocytes and ATMs from a
valuable obese bariatric surgery cohort, focusing on diabetic vs. non-diabetic comparisons in two research
aims: (1) Identify the genes and pathways by which myeloid cells are dysregulated in human obesity. I will use
a combination of powerful, unbiased high-throughput genomics platforms with novel bioinformatics tools to
identify specific pathways and regulators in SRhi myeloid cells from diabetic patients. I will use assays of
endocytosis and lysosomal function, proinflammatory cytokines, and flow cytometry to determine functional
changes in SRhi myeloid cell subtypes in diabetes. (2) Determine the specificity and efficacy of NPs for myeloid
cell modulation in human obesity. I will test internalization and impact of NPs on human SRhi myeloid cell
subtypes, determining whether they can attenuate proinflammatory signatures through cytokine assays and
RNA-seq. By completing these aims I will identify the molecular and cellular signatures mediating activation of
SRhi myeloid cells and determine efficacy of novel NP-therapeutics to modulate SRhi myeloid cells in human
metabolic disease. I will gain expertise in nanotechnology and high-throughput genomics platforms. The
mentorship team will be led by co-primary mentors Dr. Robert O'Rourke and Dr. Lonnie Shea. Dr. O'Rourke is
an expert in human obesity and clinical biosamples. Dr. Shea is an internationally recognized researcher at the
interface of regenerative medicine, drug and gene delivery, and immune tolerance. Co-primary mentors and
experts in immunometabolism, diabetes, obesity, and genomics and bioinformatics will ...

## Key facts

- **NIH application ID:** 9995489
- **Project number:** 5K01DK116928-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Lindsey Allison Muir
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $92,258
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9995489

## Citation

> US National Institutes of Health, RePORTER application 9995489, Myeloid lineage activation and reprogramming in metabolic dysfunction (5K01DK116928-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9995489. Licensed CC0.

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