Dr. Meucci's laboratory aims to identify therapeutic targets for neurodegenerative and neuroinflammatory disorders and contribute to the development of neuroprotective drugs. Her 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 substance use, the laboratory also investigates how opioids interact with the endogenous chemokine system – a crucial regulator of both immune and nervous system function.
The Meucci lab has published extensively on chemokine physiopathology in the central nervous system (CNS) and cellular/molecular mechanisms of HIV neuropathogenesis, which has revealed promising therapeutic targets against HAND and other cognitive disorders. These efforts have focused on the chemokine-receptor pairs CXCL12/CXCR4 and CX3CL1/CX3CR1, which are constitutively expressed in the CNS and regulate essential neuronal and glia functions. The lab uses in vitro, ex vivo, and in vivo model systems (i.e., primary neuronal and glial cultures, brain slice cultures, animal models, and human brain specimens) to investigate mechanisms of disease and test potential therapeutic interventions. Additional collaborative projects study chemokines roles in cancer.
Dr. Meucci’s research has been continuously funded by the NIH and other organizations since 2001, and she recently received the prestigious MERIT award from NIH-NIDA. Her most significant accomplishments have been in the following main areas (see publications tab for more details).
HIV-induced neuronal damage and potential pharmacologic targets for HAND
HIV neuropathology is a complex disorder driven by multiple effects of HIV neurotoxins on different brain cells. HIV fails to infect neurons directly, but Dr. Meucci’s early work found that neurons can express chemokine receptors like CXCR4, a co-receptor that HIV uses to infect immune cells. HIV proteins can disrupt these neuronal chemokine receptors, which normally promote brain homeostasis. These studies formed a foundation to uncover how CNS chemokine receptors contribute to HAND, and potential therapeutic approaches that target chemokine receptors and related pathways. Our recent work has examined how HIV damages neurons in a new human brain slice culture model of HIV infection.
The lab has also developed new tools and approaches to study how HIV interacts with the aging brain, as people using antiretroviral therapies often live full lifespans. As clinical studies suggest people with HAND can accumulate amyloid-β in neurons, we developed unique fusion proteins to precisely control amyloidogenic pathways in a longstanding collaboration with Dr. Renato Brandimarti (University of Bologna). These proteins take advantage of the herpes simplex virus protein US9 to deliver cargo that binds the amyloid precursor protein (APP) in subcellular organelles and diverts APP from amyloidogenic secretases. These molecular tools are helping us uncover how HIV regulates amyloidogenic pathways, and how amyloid processing contributes to HAND during aging.
Chemokine receptors in the CNS
The lab discovered that chemokines regulate a variety of critical functions in differentiated neurons, such as neuronal-glial communication, neurotransmission, and excitotoxicity. These discoveries have helped predict how chemokines contribute to normal and pathological conditions and allowed us to explore new therapeutic approaches to reduce neuroinflammation and neuronal damage in the adult brain. Recent work identified that neuronal CXCR4 signaling helps neurons form new connections within their local network, and this pathway can overcome HIV-induced neuronal disconnection and improve cognitive performance in an animal model of HAND.
The opioid-chemokine interaction in HAND
The lab found that homeostatic CXCR4 signaling is also inhibited by opiates, which revealed unexpected factors that may drive HIV neuropathology in people with substance use disorders. Opioids inhibit CXCR4 via a unique mechanism that dysregulates neuronal iron stores and causes neurons to upregulate ferritin heavy chain, an iron storage protein that also inhibits CXCR4 downstream signals. These studies have opened a new research area on how opioids regulate neuronal iron metabolism, and how iron regulates neuronal structure, function, and homeostasis. This work suggests opioid use may have much larger implications both within and outside the CNS.
Chemokine contributions to 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. Our work discovered that a novel CX3CR1 antagonist impairs breast cancer metastatic seeding to the skeleton by prolonging the cancer cells time in circulation and exposure to chemotherapy. Our more recent work uncovered that CX3CR1 expressing cancer cells are a rare subset with high expression of stemness genes, allowing them to resist chemotherapy and start new metastases. Therapeutic targeting of CX3CR1-expressing cancer cells could provide an effective approach to limit cancer progression and the metastatic cascade, a major cause of patient mortality.
Grant Funding
NIH-NIDA 2 R01 DA015014; Transformed to R37-DA015014 MERIT award, 2018-2028
Principal Investigator: Meucci
Project Title: Role of chemokine receptors in neuronal survival
NIH-NIDA 2 R01 DA032444
Principal Investigator: Meucci
Project Title: Effects of opiates on neurons and their impact on HIV neuropathology
NIH-NIDA 1 R21 DA056309
Principal Investigators: Meucci, Klase, Jackson
Project Title: Adult human brain tissue cultures to study neuroHIV
NIH-NIMH 5 T32 MH079785
Program Director: T. Burdo, PI/Co-PI-subcontract: Wigdahl/Meucci
Project Title: Interdisciplinary and Translational Research Training in NeuroHIV
NIH-NIDA 1 R61 DA058501
Principal Investigator: Gaskill, Co-Investigator: Meucci
Project Title: Defining molecular mechanisms by which stimulant evoked dopamine drives inflammation and neuronal dysfunction in neuroHIV
NIH-NIMH 1 K01 MH132466
Principal Investigator: Matt, Co-mentor: Meucci
Project Title: The role of antidepressants in central and peripheral myeloid HIV persistence and inflammation
NIH-NIDA 1 F32 DA060768
Principal Investigator: Namba, Sponsor: Barker, Co-Sponsor: Meucci
Project Title: Corticolimbic circuit and neuroimmune mechanisms of comorbid HIV and cocaine use
NIH-NIAID 1 F30 AI179472
Principal Investigator: Channer, Sponsor: Gaskill, Co-Sponsor: Meucci
Project Title: Dopaminergic immunomodulation drives macrophage inflammation during HIV infection
NIH-NCI 1 R01 CA202929
Principal Investigators: Fatatis, Meucci
Project Title: Role of CX3CR1 in breast cancer metastasis
NIH-NIDA 1 R21 DA040519
Principal Investigator: Meucci
Project Title: Effects of HIV neurotoxins on lipid rafts-associated proteins
Coulter Foundation
Principal Investigators: Fatatis, Meucci
Project Title: Small molecule compounds for the therapy of metastatic cancer
Breast Cancer Alliance
Principal Investigator: Fatatis, co-Investigators: Meucci/Salvino
Project Title: New Small molecule compounds for the therapy of metastatic cancer
NIH-NIMH 1 R21 MH097623
Principal Investigators: Waterhouse, Meucci, Torres, Gao, Shumsky
Project Title: HIV gp120 and Prefrontal Cortical Function
Restless Leg Syndrome Foundation
Principal Investigator: Padma Ponnuru, Mentor: Meucci
Project Title: A role for MEIS 1 in iron brain deficiency in RLS
US Army Public Health Command CTC/CHPPM (RFQ# 09-0344)
Principal Investigator: Meucci
Project Title: Mechanism of action of RDX neuronal toxicity
NIH-NIDA 1 R01 DA19808
Principal Investigator: Meucci
Project Title: Cellular and Molecular Mechanisms of HIV Neuropathology
NIH-NIGMS 1 R01 GM067892
Principal Investigator: Fatatis, Co-Investigator: Meucci
Project Title: Role of intracellular sphingolipids in Ca signaling
NIH-NIDA 1 F31 DA020234
Principal Investigator: Jeegar Patel, Mentor: Meucci
Project Title: Interactions of opioid and chemokine receptors systems in neurons
Drexel University Synergy Grant
Principal Investigators: Yuan (Dept. of Physics), Meucci
Project Title: A system approach to CXCR4 receptor regulation of survival pathways in neurons and glia
W.W. Smith Charitable Trust A0302
Principal Investigator: Meucci
Project Title: Cell cycle proteins and HIV neuropathogenesis
American Foundation AIDS Research 2816-30-RG
Principal Investigator: Meucci
Project Title: Role of cell cycle proteins in HIV-Neurodegeneration