RESEARCH PROGRAMS AND AFFILIATIONS
Major depression and co-morbid disorders, behavior, gene expression, genetics, pharmacogenetics, biomarkers.
My research has resulted in over 200 publications, cited over 13,000 times (h-index 57). I have contributed primarily to three lines of investigation, as follows:
- My lab has a strong track record studying the genomics of antidepressants and major depressive disorder, which started in 2000 as part of the National Institute of General Medical Sciences, NIH Pharmacogenomics Research Network (PGRN). In that project, we studied a Mexican-American population with major depression in Los Angeles. Our group conducted the first NIH-funded studies of antidepressant pharmacogenomics in Hispanics, with findings that have been independently replicated. We have examined candidate systems and pathways, including corticotropin-releasing hormone (CRH) and CRH receptor 1 (CRHR1), brain-derived neurotrophic factor (BDNF) and its receptor, NTRK2. We re-sequenced several genes, including BDNF, NTRK2, and CRHR1, and discovered a substantial number of new variants. Recently, we have identified several genes that may be associated with major depression and replicated the PHF21B gene. These new functional genetic markers have provided the basis for a provisional patent, which we are now studying at the functional neuroscience level.
- We have contributed to understanding the role of neuroendocrine/neuroimmune aspects of MDD. We have studied cytokines and immune mediators in the central nervous system, with implications for the underlying biology of major depressive disorder, and published work in this area include the localization of gene expression for interleukin 1 receptor antagonist (Il1rn), interleukin 1 receptor, type I (Il1r1), and inducible nitric oxide synthase (Nos2) in mammalian brain. We also showed that IL1RN is an endogenous neuroprotective agent. I was the first to suggest that the central and peripheral cytokine compartments are integrated, but differentially regulated. In collaboration with colleagues at Columbia University, we showed that inflammation-mediated up-regulation of secretory sphingomyelin phosphodiesterase represents a link between inflammatory cytokines and atherogenesis. We have recently focused on the role of the inflammasome in the microbiome-gut-brain axis, shedding new light on the bi-directional pathway that links gut microbiota, the inflammasome, and depressive-like behaviors.
- We have a line of endocrine research that has a special focus on the biology of human leptin. We discovered that despite being produced by a dispersed mass of fat cells, leptin is secreted in an organized manner with distinct pulsatility and circadian rhythm and that it appears to regulate the minute-to-minute rhythms of several endocrine axes, such as the hypothalamic-pituitary-adrenal axis, the hypothalamic–pituitary–thyroid axis, and the hypothalamic–pituitary–gonadal axis. We were the first to suggest that leptin may have antidepressant effects. We also advanced the concept that leptin has pro-cognitive effects in humans.