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Wylie W. Vale

 

Wylie W. Vale

Wylie W. Vale

Professor, Laboratory Head and Helen McLoraine Chair in Molecular Neurobiology
Clayton Foundation Laboratories for Peptide Biology

"Stress hormones give us added strength and endurance and make us more vigilant and ready to freeze, flee, or fight. But they can also contribute to mental and physical illness when stress is persistent. We study the role that certain peptides discovered at Salk play in regulating the stress response and are particularly interested in conceiving therapeutic approaches to mitigate stress-linked disease."

Survival depends upon an organism's ability to adapt to changing circumstances by accurately judging and appropriately responding to threats and opportunities. In stressful circumstances, the activities of the nervous, endocrine, and immune systems must be carefully coordinated in order to successfully meet serious challenges. Vale and colleagues investigate the structures, functions, regulation, and signaling mechanisms of small proteins and peptides that act as hormones, growth factors, and neurotransmitters. One of their projects focuses on the roles of the CRF network, which comprises four related peptides, two receptors and a binding protein that have distinct anatomic distributions, regulation, and physiologic actions. The first member of the family to be discovered, CRF, acts within the brain to trigger stress-mediated behavioral, hormonal, and autonomic responses. Furthermore, CRF is suspected to play a role in various stress-related disorders, including anxiety, depression, irritable bowel syndrome, and the dysphoria associated with drug and alcohol withdrawal. Enabled by findings at the Salk Institute, drugs blocking the CRF receptor have been developed by pharmaceutical companies and are now being tested for effectiveness in the treatment of anxiety, drug addiction, and depression.

Additional family members, urocortins 1, 2 and 3, have complex effects on behavior and many important actions on the cardiovascular system, gastrointestinal system, and metabolism. For example, urocortins have beneficial effects on the injured heart and are currently undergoing Phase II clinical trials in patients with acute congestive heart failure. Urocortin 3 is produced in the brain, where it regulates appetite, and in the beta cells of the pancreas, where it acts to increase production of insulin, particularly when blood sugar is too high. Urocortin 2 is produced in skeletal muscle and acts there to control the sensitivity of this tissue to insulin.

Recent elucidation of the precise structure of the hormone binding site on CRF/urocortin receptors, in collaboration with Roland Riek's group, will provide new avenues for the development of improved drugs for managing cardiovascular and metabolic diseases, including diabetes.

Lab Photo

Left to right:
Seated: Jessica Read, Debbie Doan, Kathy Falkenhagen, Marilyn Perrin, Kunal Sukhija, Joan Vaughan, Anna Pilbrow, Samantha Dettloff Standing: Naira Nurijanyan, Ratindra Rastogi, Amy Blount, Sandra Guerra, Dave Dalton, Ezra Wiater, Karsten Schmidt, Kathy Lewis, Hannah Park, Wylie Vale, Jonathan Kelber, Evan Booker, Mark Huising, Cindy Donaldson, Remy Manuel, Peter Gray, Chiahao Kevin Tsui, Nicholas Justice, Louise Bilezikjian, Wolfgang Fischer

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Wylie W. Vale

Faculty

Wylie Vale

Wylie Vale

Professor, Laboratory Head and Helen McLoraine Chair in Molecular Neurobiology
Clayton Foundation Laboratories for Peptide Biology

Wylie Vale, the Helen McLoraine professor of molecular neurobiology and professor and head of the Clayton Foundation Laboratories for Peptide Biology, is an authority on brain hormones, in particular, small proteins called peptides. Over the past two decades, he and his colleagues have discovered more than a dozen novel peptide hormones/growth factors and their receptors including corticotropin releasing factor (CRF), a key chemical in the body's response to stress.

Vale's group has identified the receptor through which CRF communicates with cells in the pituitary, brain and elsewhere. This receptor has become an important target for the pharmaceutical industry, and drugs that block CRF are now in clinical trials. Results suggest this work may lead to a new generation of antidepressant and anti-anxiety drugs. The discovery of a second CRF receptor led to the identification of three novel hormones, urocortin 1, 2 and 3, that were then shown to act through the second CRF receptor. These new hormones have powerful effects on the brain, cardiovascular system, gastrointestinal tract and metabolism.

Vale and his colleagues also have studied ovarian and testicular hormones that have opposing roles in regulating the reproductive system. These hormones, activin and inhibin, were later found to have effects on the development and growth of normal and cancerous cells, and to regulate functions such as bone and muscle growth, the development of insulin producing cells of the pancreas, and the survival of embryonic stem cells. They have discovered several receptors for this family including the activin receptor, the first member of a novel class of receptor that is involved in the action of over a dozen growth factors.

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