Daniel Marks Lab
Cachexia, or disease-associated wasting, is a common occurrence in cancer, renal failure, heart failure and other chronic diseases. This devastating state of malnutrition is brought about by a synergistic combination of a dramatic 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. There is currently no effective pharmaceutical treatment, and this disorder of energy homeostasis is poorly understood. Research in Dr. Marks' lab has led to the hypothesis that an increase in melanocortin signaling in the hypothalamus may be responsible for many of the features of illness-induced cachexia and failure to thrive. The lab has demonstrated that the growth failure and loss of lean body mass that would otherwise accompany acute and chronic disease could be reversed by pharmacological blockade of melanocortin signaling, and by genetic deletion of the type 4 melanocortin receptor (MC4-R).
Recently, these findings have been extended to demonstrate efficacy of melanocortin blockade in the cachexia of uremia due to renal failure. Dr. Marks' laboratory is now focusing on the mechanisms whereby circulating cytokines activate the central melanocortin system. This work has demonstrated that central melanocortin neurons express cytokine receptors, including the receptors for the cachexigenic cytokines leukemia inhibitory factor (LIF-R) and interleukin-1 beta (IL-1R). Furthermore, they have shown that hypothalamic POMC neurons are activated by cytokines by showing direct electrophysiological activation in an in vitro brain preparation, and induction of gene transcription in vivo. Collectively, the data generated in this lab suggests a model wherein anorexigenic hypothalamic POMC neurons are directly activated by circulating cytokines at the same time that orexigenic neuropeptide Y neurons are inhibited by this same signal. Using transgenic and knockout models, the lab is now working to demonstrate that the expression of these receptors in the hypothalamus is both necessary and sufficient for cytokine feedback to the brain.
Dr. Marks has an active clinical and basic science research program related to the problem of childhood obesity. He is currently a principal investigator on an Oregon Clinical and Translational Research Institute sponsored project investigating the genetic and physiological aspects of childhood obesity. He is also the director of the Oregon Child Health Research Center in the Department of Pediatrics. An exciting new area of research for his lab centers on a collaboration with investigators at the Oregon National Primate Research Center. These studies are focused on the role of maternal nutrition on the development of obesity in the offspring.