.Aditi Bhargava, PhD
Director of Laboratory Research, Osher Center for Integrative Medicine
Professor, Department of Obstetrics, Gynecology and Reproductive Sciences, Center for Reproductive Sciences, UCSF
“Beauty is not the only thing that lies in the eye of the beholder. Stress, too, has both perceived and real components, and like beauty, the concept of stress has evolved. I believe that the stress axis, as described by Hans Seyle, which involves the neurohormonal activation of the hypothalamic-pituitary-adrenal (HPA) axis, is constantly in “overdrive” for many people today. While some stress actually benefits the organism as a whole, this constant state of being in a perceived state of stress exacerbates myriad disease symptoms. The corticotropin-releasing factor (CRF) system, the main driving force behind the HPA axis, influences immune and non-immune cellular responses locally in the peripheral tissues that are distinct from those mediated by the action of CRF in the central nervous system.”
Dr. Aditi Bhargava serves as a mentor for postdoctoral fellows, residents, junior faculty, and summer students. Her research is funded by grants from the National Institutes of Health, private foundations, and individual donors. Dr. Bhargava is a fellow of the American Gastroenterological Association (AGAF). She serves on committees of various scientific societies, such as the Endocrine Society and the Federation of American Societies for Experimental Biology (FASEB). Her research focuses on the role of neuropeptides and their receptors in inflammation, stress, and pain. The general objective is to understand the molecular and cellular mechanisms by which corticotropin-releasing factor (CRF) family of neuropeptides and their G-protein coupled receptors regulate stress-induced cellular signaling.
An estimated 57 million people in the US alone suffer from stress-related disorders. Twice as many women as men suffer from these conditions, which include autoimmune disorders, anxiety and depression. The same disease has gender-specific outcomes, but the cellular basis for these gender differences is not understood. The CRF system consists of the neuropeptides CRF and Urocortins 1-3 (Ucn1-3), and two G protein-coupled receptors (GPCRs), CRF1 and CRF2. The CRF family coordinates stress responses by acting both as a hormone to initiate the hypothalamic-pituitary-adrenal axis and as a neuromodulator in the brain and the periphery. However, the precise role of the CRF system in mediating gender-specific cellular signaling and stress responses has yet to be elucidated.
With acute or prolonged stress, CRF responses in the brain are more likely to shift into a dysregulated state in females. Others and we have shown that increased Ucn1 expression correlates with inflammatory resolution and protects against inducible inflammation. In contrast, CRF2 dysfunction exacerbates inflammation and delays healing. Despite the preponderance of stress-related diseases in females, use of female animal subjects is perpetually lacking gender-specific molecular pathogenesis in disease responses remain vastly understudied. CRF-related therapeutics have been tested in clinical trials to treat major depression, post-traumatic stress disorder, cardiac injury, congestive heart failure and irritable bowel syndrome. Most of the therapeutics, while extremely promising in animal models, were ineffective in clinical trials because the animal studies were not done in both genders.
The work in Dr. Bhargava’s lab is characterized by its use of male and female animals and side-by-side comparison of cellular components that determine gender-specific responses. They use a combination of technically challenging cell biology approaches, such as mass spectrometry, electron microscopy, and deep sequencing, to identify and localize cellular interacting partners in tissue samples obtained from in vivo animal models of human disease and patient tissues.