The overall goals in Dr. Meucci's laboratory are to identify targets for novel therapeutic approaches against neurodegenerative/neuroinflammatory disorders and contribute to the development of neuroprotective drugs. Research efforts over the last two decades have primarily focused on HIV-associated neurocognitive disorders (HAND), with a main interest in the interplay of host, viral and environmental factors in neuropathology. Due to the close link between HIV infection and drug abuse, an active area of research in the laboratory is the interaction of opiates with the endogenous chemokine system – a crucial regulator of both immune and nervous system function.
Work from the Meucci lab has significantly contributed to the current knowledge of chemokine physiopathology in the central nervous system (CNS) and to the identification of cellular and molecular mechanisms of HIV neuropathogenesis, revealing promising therapeutic targets against HAND and other neurodegenerative disorders. These efforts have focused on the CXCL12/CXCR4 and the CX3CL1/CX3CR1 chemokine-receptor pairs, which are both constitutively expressed in the CNS and involved in essential neuronal and glia functions. The experimental approaches used in the lab include in vitro, ex vivo, and in vivo model systems (i.e., primary neuronal and glial cultures, brain slices, animal models, and human specimens) aimed to investigate mechanisms of disease at the cellular/molecular and system level. Additional collaborative projects relate to the role of chemokines in cancer.
This research has been funded by the NIH and other organizations since 2001, and the most significant accomplishments have been in the following main areas.
Mechanisms of HIV-induced neuronal damage and identification of potential pharmacologic targets for HAND
Innovative discoveries about the multiple effects of HIV proteins on different brain cells revealed the complexity of the mechanisms underlying HIV-neuropathology. These studies have drawn the attention of the scientific community to the necessity of a multifaceted approach for the treatment of HAND. This supports the need for adjuvant neuroprotective therapies targeting both neuronal and glial cells in antiretroviral-treated patients.
Chemokine receptors in the CNS
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.
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.
Read Dr. Meucci's Women in Medicine and Science Committee highlight.