PQ6: Lipocalin-2 as a therapeutic target for prevention of cancer cachexia

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Project Summary: Illness behaviors, metabolic disturbances, and cognitive decline are common in patients with chronic systemic diseases, and contribute substantially to quality of life and ultimate survival. Other illness-induced morbidities including anorexia and lethargy also compromise the ability of patients to recover from life-saving or extending interventions, and diminish the motivational drive to aggressively battle the underlying 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. Cognitive decline is common in all chronic diseases, and can be a presenting complaint in cancer patients, even prior to initiation of therapy. Our laboratory is dedicated to unraveling the basic mechanisms whereby cancer triggers neuroinflammation, a key driver of cachexia and cognitive decline in patients with cancer. In this proposal, we will focus on understanding the scope and mechanism by which systemic illness induces the production of a molecule called lipocalin-2, that in turn acts on the brain to cause loss of appetite and cognitive decline. The significance of this proposal resides in its unique combination of our historical focus on neuroendocrinology and neuroinflammation, with new collaborations and efforts directed at understanding the extent and mechanisms of anorexia and neurocognitive decline in patients with cancer. The long-term goal of our research is to gain mechanistic understanding of the acute illness response and how it is transitioned into chronic neuroinflammation in all cancer types, in order to develop more effective therapeutic interventions.