# The Role of Leukocytes in the Hypothalamus in Cancer Cachexia

> **NIH NIH F30** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $574

## Abstract

Project Summary
Cachexia is a devastating state of malnutrition brought about by a synergistic combination of decreased
appetite and increased metabolism of fat and lean body mass. While many chronic diseases such as cirrhosis,
Alzheimer's disease, and congestive heart failure are associated with cachexia, it is particularly prevalent in
pancreatic ductal adenocarcinoma (PDAC). There are currently no effective treatments for PDAC-associated
cachexia, and its mechanisms are poorly understood. Our lab previously identified the actions of the
inflammatory cytokines IL-1β and TNFα on hypothalamic neurons and their role in driving cachexia symptoms.
Cytokines are produced in the hypothalamus during states of systemic inflammation, and injection of IL-1β and
TNFα into the brain recapitulate the signs and symptoms of cancer cachexia. However, chronic central
administration of these cytokines leads to rapid desensitization and loss of sickness response. Furthermore,
the source of cytokines in the central nervous system (CNS) during cachexia is not known.
 Leukocytes produce cytokines during numerous chronic diseases, yet their role in cachexia is unknown.
Circulating immune cells infiltrate the brain and are important mediators of sickness response in states of
systemic stress such as inflammatory liver disease and bacterial infection. However, the role of infiltrating
leukocytes in the brain during cancer cachexia has not been investigated. I found that, in a murine model of
PDAC-associated cachexia, thousands of peripheral immune cells infiltrate the brain. The majority of these
cells are neutrophils. Furthermore, the chemokine CCL2, which is important for myeloid cell recruitment to the
brain during states of peripheral and central inflammation, is highly upregulated in the brain during PDAC.
Lastly, a large percentage of neutrophils in the brain express CCR2 (the receptor for CCL2) and animals
lacking CCR2 have a 43% decrease in neutrophils in the brain during PDAC.
 My hypothesis is that during PDAC, peripheral leukocytes are recruited to the brain by the chemokine
CCL2 and are key drivers of chronic hypothalamic inflammation and subsequent cachexia. This project
proposes to first assess for the presence of infiltrating immune cells in other organs affected in cachexia during
PDAC. It will then determine if neutrophils are necessary for cachexia by depleting these cells during PDAC. It
will also determine if immune cell infiltration into the brain is necessary for PDAC-associated cachexia by
blocking leukocyte migration. Lastly, this project proposes to selectively inhibit CCL2 in the brain using genetic
and pharmacologic techniques to determine if CCL2 is important for immune cell recruitment to the brain,
maintaining chronic hypothalamic inflammation, and cachexia during PDAC.
 Taken together, achieving the goals of this project will: 1) Enhance our understanding of cachexia, 2)
provide multiple novel therapeutic targets for cachexia, and 3) intro...

## Key facts

- **NIH application ID:** 10115628
- **Project number:** 5F30CA213745-04
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Kevin Glenn Burfeind
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $574
- **Award type:** 5
- **Project period:** 2018-03-01 → 2021-03-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115628

## Citation

> US National Institutes of Health, RePORTER application 10115628, The Role of Leukocytes in the Hypothalamus in Cancer Cachexia (5F30CA213745-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10115628. Licensed CC0.

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