Research Interests
Our research aims to characterize the physiological and pathological actions of chemokines in the central nervous system (CNS) in order to foster the development of new therapeutic approaches against neuroinflammatory and neurodegenerative disorders, including neuroAIDS.
Experimental Methods
We examine the effects of chemokines and viral proteins using different methods including traditional biochemical/molecular biology techniques and novel imaging and proteomics approaches, as briefly described below. Primary cultures of rat and human central neurons are used as a model for the study of chemokine receptors naturally expressed by neurons. Alternative models include neuronal human cell lines expressing specific chemokine receptors. In addition, small animal models and post-mortem brain tissue samples from control and HIV-infected individuals are used for the analyses of specific pathways of interest in vivo/ex vivo.
NeuroHIV and Chemokine Receptors
Novel roles and regulatory factors: The lab has identified novel roles of chemokines in differentiated neurons, such as regulation of neuronal-glial communication, neurotransmission, and excitotoxicity. These findings elucidated some of the molecular players that lead to neuronal injury. By revealing the link of certain chemokine receptors to neuronal survival and function, these discoveries have been instrumental in predicting potential consequence of chemokine alteration or manipulation under normal and pathological conditions, and in the exploration of new therapeutic approaches to reduce neuroinflammation and neuronal damage in the adult brain.
Synaptodendritic Injury in HAND
Despite the benefits of current antiretroviral treatments, the neurological complications of HIV infection remain an important and unmet medical and social need. Drug abusers, particularly injection drug users, represent a significant group of HIV-infected patients. These individuals, whose adherence to antiretroviral therapy is generally poor, often present with a more dramatic progression to AIDS and neuroAIDS. Opiates can accelerate HIV neuropathology by acting on immune and neural cells; however, the mechanisms involved are unclear. Characterization of these mechanisms will yield new insights for the development of neuroprotective therapies in HIV patients.
Impact of the opiate-chemokine interaction in HAND
Discoveries concerning the regulation of the CXCR4 chemokine receptors by opiates, including morphine, have revealed unexpected factors responsible for HIV neuropathology that may be particularly relevant to the HIV+ population of drug users. Importantly, these studies have unveiled a novel function of the iron storage protein ferritin heavy chain, which may have much larger implications both within and outside the CNS.
Chemokine-based methods for inhibiting cancer metastasis
Long-term collaborative studies with Dr. Alessandro Fatatis (College of Medicine) have focused on the role of the chemokine receptor CX3CR1 in skeletal metastasis. Work with other collaborators (Dr. Benovic at Thomas Jefferson University and Dr. Rubin at Washington University in St. Louis) has examined alterations of CXCR4 signaling in cancer cells. These efforts have recently led to the generation of patented small molecule compounds (synthesized by Dr. Salvino, College of Medicine) that show promise for the treatment of skeletal metastasis in breast and prostate cancer patients.