Daniel L. Marks - US grants

[unreadable] DESCRIPTION (provided by applicant):To achieve normal growth, development, and quality of life, individuals must maintain adequate intake of nutrition and be free from prolonged metabolic derangement. Unfortunately, people affected with either acute or chronic diseases often show disorders of nutrient balance. In some cases, a devastating state of malnutrition known as cachexia arises, brought about by a synergistic combination of a dramatic decrease in appetite and an increase in metabolism of fat and lean body mass. This combination is found in a number of disorders including cancer, cystic fibrosis, AIDS, rheumatoid arthritis, and renal failure, and is an important determinant of morbidity and mortality in these conditions. Experimental models have demonstrated the importance of cytokines in mediating illness-induced anorexia and cachexia but the neuronal systems involved in transducing this signal have not beep fully defined. Work in this lab and in others has demonstrated that hypothalamic melanocortin receptors play a critical role in regulating feeding behavior, linear growth, metabolic rate, and insulin sensitivity. Stimulation of the hypothalamic melanocortin-4 receptor (MC4-R) produces relative anorexia, while prolonged antagonism of this receptor stimulates feeding and results in excessive weight gain and growth. More recently, we have been able to demonstrate that in both acute and chronic disease models, blockade of the MC4-R results in a dramatic attenuation of cachexia. Current research goals fall into two general areas as described in this grant. First, we will examine the contribution and unique function of both the melanocortin-4 receptor (MC4-R) as well as as well as the MC3-R in acute and chronic cachexia. Second, the mechanisms by which circulating cytokines and tumor-derived factors activate the hypothalamic melanocortin system will be defined. Additionally, the process of habituation to cytokine-mediated anorexia will be investigated in the context of central melanocortin function. Ultimately, this work may lead to investigation of drug therapy for this widespread medical problem.

To achieve normal growth, development, and quality of life, individuals must maintain adequate intake of nutrition and be free from prolonged metabolic derangement. Unfortunately, people affected with either acute or chronic diseases often show disorders of nutrient balance. In some cases, a devastating state of malnutrition known as cachexia arises, brought about by a synergistic combination of a dramatic decrease in appetite and an increase in metabolism of fat and lean body mass. This combination is found in a number of disorders including cancer, cystic fibrosis, AIDS, rheumatoid arthritis, and renal failure, and is an important determinant of morbidity and mortality in these conditions. Experimental models have demonstrated the importance of cytokines in mediating illness-induced anorexia and cachexia but the neuronal systems involved in transducing this signal have not been fully defined. Work in this lab and in others has demonstrated that hypothalamic melanocortin receptors play a critical role in regulating feeding behavior, linear growth, metabolic rate, and insulin sensitivity. Stimulation of the hypothalamic melanocortin-4 receptor (MC4-R) produces relative anorexia, while prolonged antagonism of this receptor stimulates feeding and results in excessive weight gain and growth. More recently, we have been able to demonstrate that in both acute and chronic disease models, blockade of the MC4-R results in a dramatic attenuation of cachexia. We have also demonstrated that blockade of the melanocortin-3 receptor (MC3-R) leads to enhanced disease-associated cachexia whereas stimulation of the MC3-R leads to increased food intake. Current research goals fall into two general areas as described in this grant. First, we will examine the contribution and unique function the MC3-R in acute and chronic cachexia. Second, the mechanisms by which circulating cytokines and tumor-derived factors activate the hypothalamic melanocortin system will be defined. Additionally, the process of habituation to cytokine-mediated anorexia will be investigated in the context of central melanocortin function. Ultimately, this work may lead to investigation of drug therapy for this widespread medical problem.

DESCRIPTION (provided by applicant): This application proposes to continue a training program in Pediatric Endocrinology that will provide M.D. and M.D./Ph.D. pediatricians with rigorous training in biomedical research to prepare them for successful careers in academic medicine. The training program will take advantage of the research expertise and close collaborative interactions between several components of Oregon Health & Science University including the Departments of Pediatrics and Medicine, the Vollum Institute for Advanced Biomedical Research, the Oregon Regional Primate Research Center, the Research Division of the Shriners Hospital for Crippled Children and the Oregon Clinical and Translational Research Institute. Faculty mentors recruited from these research facilities represent leaders in the field f endocrinology and diabetes and will constitute a powerful scientific base for the development of accomplished pediatric endocrine physician-scientists. The proposed program is a continuation of our current successful three year training program. The first year consists of the required clinical component Pediatric Endocrinology Fellowship training in addition to an introduction to research. The first year includes an introduction to research techniques, experimental design, responsible conduct of scientific investigation and an introduction to clinical research. The second and third years of training are devoted to intensive training in either clinical or basic science research. The clinical research track will be coordinated with the OHSU Human Investigations Program (HIP). Clinical research track trainees will be encouraged to obtain a Masters in Clinical Research as part of their training. Basic science research track trainees will be exposed to some clinical research through the HIP program but will primarily focus their efforts on a basic science project during their 2 research years. During the research years, trainees will regularly attend their mentor's laboratory meetings and relevant seminars and journal clubs, and will be expected to present their research locally and at national meetings. One new fellowship applicant will be chosen each year from M.D. or M.D./Ph.D. candidates that have completed three years of Pediatrics residency with special attention to recruitment of racial and ethnic minorities. Two years of support are requested for each selected fellowship applicant to fund the research training in the second and third years of training.

DESCRIPTION (provided by applicant): 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.

Project Summary: Illness behaviors and metabolic disturbances are common in pancreatic cancer patients, and may lead to wasting or cachexia. 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 life-saving or extending interventions, and diminish the motivational drive to aggressively battle the condition. Although cachexia in cancer patients was described more than two thousand years ago, the central mechanisms underlying this disorder are poorly understood. Furthermore, there is currently no effective pharmaceutical treatment. Our laboratory is dedicated to unraveling the basic neuroscience of cachexia. In this proposal, we will focus on understanding the scope and mechanism by which signals of pancreatic cancer development 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 the role of extracellular vesicles in neuroinflammation. 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.