Cachexia, or disease-associated wasting, is a common occurrence in cancer, renal failure, and infectious disease. This devastating state of malnutrition is brought about by a synergistic combination of a decrease in appetite and an increase in metabolism of fat and lean body mass. The severity of cachexia in many illnesses is the primary determining factor in both quality of life, and in eventual mortality. Other illness-induced morbidities including lethargy also compromise the ability of patients to recover from potentially life-saving or extending interventions, and diminish the motivational drive to aggressively battle the condition. Although cachexia in chronic disease was described more than two thousand years ago, the central mechanisms underlying this disorder of energy homeostasis are poorly understood. Furthermore, there is currently no effective pharmaceutical treatment. Our laboratory has dedicated the last decade to unraveling the basic neuroscience of cachexia. In this proposal, we will focus on understanding the scope and mechanism by which peripheral inflammatory insults are received, amplified, and maintained by the hypothalamus. The significance of this proposal resides in its unique combination of our historical focus on neuroendocrinology and behavior, with new collaborations and efforts directed at understanding proximal neuroinflammatory events. The long-term goal of our research is to gain mechanistic understanding of the acute illness response and how it is transitioned into chronic inflammation-associated cachexia in order to develop more effective therapeutic interventions.

Public Health Relevance

Involuntary weight loss, anorexia, fatigue, and loss of muscle are common in patients with cancer. New research demonstrates that these problems limit quality of life for cancer patients, and also are a significant contributor to risk of death. Our studies are designed to investigate the way in which cancer leads to these disabling changes in behavior and metabolism to better understand how this condition might be treated.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA184324-01
Application #
8680933
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Spalholz, Barbara A
Project Start
2014-07-01
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Portland
State
OR
Country
United States
Zip Code
97239
Girardet, Clémence; Mavrikaki, Maria M; Stevens, Joseph R et al. (2017) Melanocortin-3 receptors expressed in Nkx2.1(+ve) neurons are sufficient for controlling appetitive responses to hypocaloric conditioning. Sci Rep 7:44444
Michaelis, Katherine A; Zhu, Xinxia; Burfeind, Kevin G et al. (2017) Establishment and characterization of a novel murine model of pancreatic cancer cachexia. J Cachexia Sarcopenia Muscle 8:824-838
Krasnow, Stephanie M; Knoll, J Gabriel; Verghese, Santhosh Chakkaramakkil et al. (2017) Amplification and propagation of interleukin-1? signaling by murine brain endothelial and glial cells. J Neuroinflammation 14:133
Goloviznina, Natalya A; Verghese, Santhosh Chakkaramakkil; Yoon, Young Me et al. (2017) Mesenchymal stromal cell-derived extracellular vesicles promote myeloid-biased multipotent hematopoietic progenitor expansion via Toll-like receptor engagement. J Biol Chem 292:3541
Burfeind, Kevin G; Michaelis, Katherine A; Marks, Daniel L (2016) The central role of hypothalamic inflammation in the acute illness response and cachexia. Semin Cell Dev Biol 54:42-52
Kram, David E; Krasnow, Stephanie M; Levasseur, Peter R et al. (2016) Dexamethasone Chemotherapy Does Not Disrupt Orexin Signaling. PLoS One 11:e0168731
Goloviznina, Natalya A; Verghese, Santhosh Chakkaramakkil; Yoon, Young Me et al. (2016) Mesenchymal Stromal Cell-derived Extracellular Vesicles Promote Myeloid-biased Multipotent Hematopoietic Progenitor Expansion via Toll-Like Receptor Engagement. J Biol Chem 291:24607-24617
Zhu, Xinxia; Levasseur, Pete R; Michaelis, Katherine A et al. (2016) A distinct brain pathway links viral RNA exposure to sickness behavior. Sci Rep 6:29885
Burfeind, Kevin G; Yadav, Vijayshree; Marks, Daniel L (2016) Hypothalamic Dysfunction and Multiple Sclerosis: Implications for Fatigue and Weight Dysregulation. Curr Neurol Neurosci Rep 16:98