Addressing the NeuroAIDS Epidemic
HIV-infected people, over 39 million worldwide, are living longer and have fewer opportunistic infections as a result of successful antiretroviral therapies (ART). Despite this success, neurologic complications of HIV infection have not declined. HIV enters the central nervous system (CNS) early after infection and despite successful therapy, persists within the CNS. More than 50% of HIV-positive people exhibit some form of HIV-associated neurocognitive impairment (HAND) as a result of HIV within the brain and the ensuing low-level inflammation and neuronal damage.
NeuroAIDS is a major public health issue for which there are currently no biomarkers or therapies. The laboratory of Joan W. Berman, PhD,examines mechanisms of HIV neuropathogenesis and potential therapies to reduce viral seeding and CNS inflammation.
The Berman laboratory studies human monocyte and T cell transmigration across the human blood brain barrier (BBB), which monocyte subset preferentially crosses the BBB, and the junctional proteins and chemotactic factors that mediate this process. Dr. Berman and her team examine tissues, cells, and fluids from HIV-positive individuals for biomarkers, junctional proteins, inflammatory factors, functional properties, and predictors of HAND. The investigators use sophisticated molecular techniques to detect HIV RNA/DNA in PBMC and tissues obtained from these individuals, and correlate the findings with neuroimaging studies, neurocognitive testing, and clinical data from them. The investigators use single-cell RNA sequencing analyses to characterize the cells that are HIV positive.
The goal: to identify biomarkers for HAND and therapeutic targets to limit/eliminate CNS infection, HIV reservoirs within the brain, and subsequent damage.
In addition, the Berman laboratory is characterizing the impact of substance abuse, specifically opioids and methamphetamine, on neuroAIDS, BBB permeability, and macrophages/microglia, as well as the role of autophagy in HAND and influence of substance abuse on autophagy. Studies are also being done to understand the mechanisms by which buprenorphine, a therapy for heroin addiction, mitigates neuroinflammation, CNS damage, and cognitive deficits in the context of HIV infection.
Cancer, Immunosenescence in Aging: Paving the Way for New Drug Therapies
The laboratory of Fernando Macian, MD, PhD, focuses on four areas of research. These include: regulation of T cell tolerance; reversal of tumor-induced T cell tolerance as an immunotherapeutic approach; autophagy and T cell function; and aging in the T cell compartment.
One mechanism of peripheral lymphocyte tolerance is anergy, an intracellular process in which antigen receptors become un-coupled from their downstream signaling pathways. Anergic lymphocytes remain in a state of non-responsiveness that prevents harmful responses to self-tissues.
Dr. Macian and his team have shown that tolerant T cells express a novel set of anergy-associated genes. Their analysis of the specific genes activated in anergic T cells supports the existence of distinct mechanisms of tolerance induction, including interference with signaling pathways coupled to antigen receptors and transcriptional modulation. The Macian lab is studying the role of these processes in peripheral T cell tolerance, and how they may be involved in regulatory T cell-mediated suppression and T cell exhaustion.
Cell homeostasis requires a regulated balance between synthesis and degradation of cellular components. Autophagy, a catabolic pathway for degradation in lysosomes and recycling of intracellular components, is a major system involved in cellular quality control. Dysregulation of autophagy has been proposed as a cause of altered function of different organs and tissues in the elderly and of the development of age-related pathologies. The Macian lab is characterizing the role of different forms of autophagy in T cells and analyzing the consequences of altered autophagic activity with age as a mechanism to explain the diminished T cell function that characterizes immunosenescence.
Revealing the Mechanisms of Normal and Malignant Plasma Cells
The laboratory of David R. Fooksman, PhD, focuses on various aspects of normal and malignant plasma cell physiology: how these cells develop, migrate, survive and function in vivo, and in particular in the bone marrow. The bone marrow (BM) is a critical microenvironment that supports and constrains these cells; by understanding the interactions, Dr. Fooksman and his team aim to develop more-effective treatments for cancer as well as better vaccines.
To investigate these questions, the Fooksman laboratory employs cellular immunology techniques, sophisticated mouse models, and custom two-photon intravital imaging tools to visualize and manipulate cells in situ using live mice.
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Elucidating the Mechanisms of Multiple Sclerosis
Multiple Sclerosis (MS) is a debilitating neurologic disease affecting young adults. A central issue for treatment is how cell signaling pathways regulate oligodendrocyte cell survival and remyelination after the inflammatory response. Oligodendrocytes are the myelinating cells of the central nervous system (CNS); their fine-tuning and survival is paramount for normal neurological function.
Toward this goal, the laboratory of Bridget Shafit-Zagardo, PhD, has used a molecular approach to identify several genes implicated in signaling pathways that regulate oligodendrocyte and neuronal survival. One group of genes encodes proteins belonging to the Tyro3/Axl/Mer (TAM) family of receptor tyrosine kinases. TAM are located at the cell surface and bind the growth factor growth arrest-specific protein 6 (Gas6). Gas6 binding serves as a signal that activates downstream signaling proteins that have multiple functions in the oligodendrocyte, including protection of oligodendrocytes from cell death via the PI3 kinase/AKT pathway. Gas6 signaling is involved in clearance of apoptotic cells and myelin debris following an immune attack. In established MS lesions, increased protease activity upregulates Axl and Mer and negatively correlates with Gas6, reducing the interaction of Gas6 with surface-bound receptors.
Dr. Shafit-Zagardo and her team have initiated in vivo studies to determine whether Gas6 is therapeutic following an inflammatory attack in the CNS in mouse models of neuroimmune demyelination. They are also examining the role of AKT3 in the CNS and in T-cell cell function.
Other ongoing projects involve applying techniques of molecular & cell biology, biochemistry, immunocytochemistry, confocal and electron microscopy to address questions concerning the structure, function and regulation of myelination in the normal CNS and remyelination following neuroimmune injury.