Clayton Foundation Laboratories for Peptide Biology
Dr. Frederik Paulsen Chair in Neurosciences
Jean E. F. Rivier, the Dr. Frederik Paulsen Chair in Neurosciences and professor in The Clayton Foundation Laboratories for Peptide Biology, studies the chemistry and structure of hormones produced by the brain. These hormones, produced in extremely minute amounts, are powerful factors in stimulating growth and initiating the body's complex response to stress. They also orchestrate reproductive activity and control many other essential physiological responses.
His lab plays a principal role in the design of molecules which can either interfere with or mimic the effects of brain hormones, including corticotropin releasing factor, which has been linked with stress. Many of these novel molecules are useful in treating diseases that result from disruption of the brain's intricate functions, including depression and anxiety. Rivier and collaborators recently characterized toxins from the venom of fish-eating sea snails that have proven valuable neuroscience research tools.
Like a central command center, the brain area known as the hypothalamus sends out "master" brain hormones, which regulate basic bodily functions. Many of these hypothalamic hormones, including the "stress hormones" corticotropin releasing factor (CRF) and the urocortins (Ucn), as well as their two receptors (CRFR1 and CRFR2), were characterized at the Salk Institute. Because of their broad distribution, CRFs and CRFRs mediate numerous complementary stressrelated endocrine, autonomic, metabolic, immune, cardiovascular, gastrointestinal, and cutaneous pathologies.
To test whether molecules that block CRF's functions may induce remissions, Rivier, in collaboration with Salk colleagues Wylie Vale and Catherine Rivier, developed a series of very effective CRF antagonists. Working with Lixin Wang, Mulugeta Million, and Yvette Taché at UCLA, Rivier and his team then tested the effects of a potent and long-acting version in mice that overexpress CRF. Without treatment, these mice develop symptoms that are typical of Cushing's syndrome, such as thinning of the skin, loss of fur, and fat accumulation at the midsection of the body as they get older. When treated with a CRF antagonist, however, their fur immediately starts to regrow.
Under stressful conditions, the body responds initially by mounting a multipronged counterattack that normally deals successfully with acute challenges but more likely than not will fail in the face of chronic challenges. When unsuccessful, the body's defense mechanisms such as the immune system become compromised, triggering a recurrence of the disease. If the chronic stress response is mitigated either psychologically or pharmaceutically, Rivier believes that those systems recover their ability to deal with the insult, thus triggering a remission–the first step toward full recovery. He is now testing this hypothesis in animal models, including prematurely weaned pigs, which suffer from stress-induced diarrhea. Initial promising results indicate that CRF antagonists could play an important role in treating irritable bowel syndrome and, hypothetically, most other conditions initiated by or relapsing as a result of stress.