Drs. Tony Yaksh (Anesthesiology), Yury Miller (Medicine), MariPat Corr (Rheumatology) at the University of California, San Diego have an established, NIH supported, collaborative research program on the biology of pain states occurring after persistent inflammation, and in mono and polyneuropathies. Specifically, we are seeking a highly motivated individual to join our group examining the role of innate and adaptive immune signaling in regulating afferent and spinal excitability. Several specific projects are ongoing.
1. Arthralgia and tissue injury impacts quality of life because of joint dysfunction and associated pain. The K/BxN model of arthritis produces a long lasting, but reversible inflammation of the joint accompanied by an early onset allodynia that persists long after the resolution of inflammatory indices. The late phase of the model appears to represent a transition to a pain state with a neuropathic phenotype mediated by innate immune signaling (Christianson et al Neuroscience 152:2881-91, 2011) Mechanisms of this transition and the role of sex are a particular focus of this work. The work currently involves detailed characterization of the phosphoproteomics of the early and late pain states and the effects of drugs on that transition.
2. Neuropathic pain states have an extraordinary negative impact on quality of life. Activation of receptors involved in neuroinflammation and the development of neuropathic pain depend on integrity of membrane lipid raft microdomains. Apolipoprotein A-I binding protein (AIBP) reduces lipid raft abundance by augmenting cholesterol efflux. We have found that AIBP prevents and reverses neuropathic pain, including that in the mouse model of chemotherapy-induced peripheral neuropathy. The mechanism involves binding of AIBP to Toll-like receptor-4 (TLR4). Consequently, TLR4 occupancy in lipid rafts, TLR4 dimerization, and microglia inflammatory responses are all reduced in vivo and invitro. Future directs focus on the release of endogenous TLR4 ligands though assessment of dimerization and factors governing that release.
3. Acetominophen is a classic antihyperalgesic agent, the mechanism of action of which is not understood. In response to the prescription opioid abuse epidemic, pharma collaborators undertook to create analgesically efficacious molecules which structurally mimic acetaminophen (APAP). with dose dependent effects upon hyperalgesia and allodynia in preclinical models of pain. This work focuses on the mechanisms of action of APAP and these structural mimetics with a broad range of physiologic manipulations and an unbiased phosphoproteomics analysis examining drug effects pain evoked dorsal horn phosphorylation profiles.
The applicant will have publications showing research experience in cell and molecular techniques. Experience with DRG neuronal and glial cell cultures, calcium imaging and recording are highly desirable skills. In vivo animal handling and drug delivery skills are important. The applicant will be directly involved with translational work aimed at developing pain therapeutics.
About Department of Anesthesiology, University of California San Diego
Dr. Tony L. Yaksh: Purdue University (PhD 1971), U.S. Army (1971-73), University of Wisconsin (1973-76), University College London (1976-77), Mayo Clinic, Rochester, MN (1977-1988). He is Professor in Anesthesiology at UC San Diego (1988-present). His studies (> 800 papers) provide a basis for understanding the pharmacology of pain processing. He has >46,000 citations in >26,000 papers. He ha...s mentored over 100 postdoctoral trainees and has been funded consistently by NIH since 1977. He has received many awards including from the American Pain Society, the International Association for the Study of Pain and the Swedish Society of Medicine. He has twice received the Javitz award.
My laboratory at Mayo Clinic (1976 to 1988) and at the University of California San Diego (1989 - present) has been continuously involved in NIH-supported research on the mechanisms of pain and analgesia. A continuing thread of this ongoing work has first been the role of lipid mediators in pain processing and more specifically the contribution of innate immunity in spinal systems. A continuing thread of this ongoing work (>20 papers) has been the contribution of inflammatory cascades and innate immunity in these spinal systems. Our group, in an extensive collaboration with Dr. Maripat Corr at UCSD demonstrated that KO of TLR4 signaling and spinal TLR4 blockers prevented the transition from an acute inflammation to a chronic neuropathic like pain state and the differential role of sex in this cascade. Our recent work looking at cell specific KO of an important link in this signaling cascade emphasize the importance of this cascade in the development of a chronic pain state. I look forward to working with Dr. Corr in pursuing the work outlined in this proposal. We have an established track record of productive collaboration and co-mentoring students and fellows.