The now chronic nature of HIV has been a major advancement in AIDS care. While HIV infected individuals are living longer, damaging effects of HIV persist in the brain and may interact with other neurodegenerative disorders. The CHAIN Center will research new ways to diagnose, predict, treat and prevent brain damage induced by HIV via a systems biology approach.
Publications resulting from the CHAIN grant.
The Administrative Core is dedicated to carrying out the mission of the CHAIN Center by providing the leadership and resources to facilitate multidisciplinary, state-of-the-science research on neuroAIDS and mental health.
Personnel will lead, supervise and coordinate the actions of the Center; and monitor and evaluate the work of the cores and investigators. The Administrative Core will facilitate collaborative efforts, and organize and implement input and recommendations from the Advisors. The Core will continue its responsibility for maintaining the Center’s focus on contemporary issues in neuroAIDS and mental health while sustaining an environment in which innovative and significant work is performed.
The Administrative Core will provide accountability for the research performed and funds used in support of our work. It is committed to creating and maintaining a stimulating intellectual environment and providing a research and administrative infrastructure conducive to maximize interdisciplinary neuroAIDS research.
This core will provide biophysical based assessments for CHAIN investigators. Both state-of-the-art imaging, including quantitative magnetic resonance imaging (MRI), MR spectroscopy (MRS) and single photon emission computed tomography (SPECT), and electrophysiological methods, including patch clamping and extracellular analysis synaptic activity will be available. Two 7-Tesla small animal MRI/S systems will provide quantitative neuroimaging and/or superparamagnetic iron oxide (SPIO) labeled cell tracking on rodent models of HIV-1 associated neurodegenerative disorder (HAND).
The Bioimaging Core methods also include quantitative mapping of blood-brain barrier permeability, quantitative arterial spin labeled perfusion mapping, and quantitative proton MRS (1H MRS).
The electrophysiology equipment and expertise will allow investigators access to state-of-the-art in vitro and in vivo approaches for studying how immune deficiency virus, viral products, cytokines, and cytotoxins, as well as genetic over- or under-expression of these elements alter molecular, cellular and synaptic physiology of neurons and brain regions believed to be involved in neuroAIDS.
The techniques in the core as a whole will also support developmental therapeutic studies relevant to microglial activation in HAD. The results obtained from this core will have direct applicability for determining the mechanisms and monitoring the course of HIV infection in its chronic stage.
Our overriding goal is to assist CHAIN Center PIs and other researchers interested in neuroAIDS in determining and characterizing changes of CNS function as they develop in the various in vitro and in vivo models of neuroAIDS, and in exploring therapeutic potentials aiming at ameliorating or reversing such functional changes.
This core will provide tissue culture and animal models for CHAIN investigators. The objectives of this core are to isolate and propagate primary human leukocytes (monocytes and peripheral blood lymphocytes and to provide rodent and primate models of CHAIN. Rigorous quality control measures are in place for this well-integrated core.
Primary human leukocytes will be fractionated into monocytes and lymphocytes from HIV-1, 2 and hepatitis B and C seronegative donors by centrifugal elutriation. Human glia (microglia and astrocytes) and/or neurons will be obtained from fetal tissues. The neurons and glia from human brain tissue will be purified, characterized and provided for experiments. These will provide data for common endpoints of disease. In toto, this ‘cell, tissue, and animal core’ will provide all the biological specimens necessary to address research objectives of the center research programs and utilize the carefully controlled specimens obtained through this infrastructure to investigate neural immunity and its links to CHAIN.
The techniques in the core as a whole will also support neuroimmunological studies relevant to microglial activation in CHAIN. The results obtained from this core will have direct applicability for determining the mechanisms and monitoring the course of HIV infection in its chronic stage.
The overriding goal is to assist CHAIN PIs and other researchers interested in neuroAIDS in determining and characterizing changes of CNS function as they develop in the various in vitro and in vivo models of neuroAIDS, and in exploring therapeutic potentials aiming at ameliorating or reversing such functional changes.
The aim of the Developmental Core is to provide a limited amount of research (seed) funds to support preliminary studies by investigators who wish to try novel approaches to the study of the chronic effects of HIV on the brain and interactions with aging.
The goal is to allow for the generation of initial findings to add in obtaining independent grant support for the investigator and thus bring new investigators and approaches to the field.
Grant applications will be solicited, external reviewed, and awarded for 1-2 year periods. Funds will be allocated per the investigators request and the availability of the CHAIN Center resources. All applicants will receive mentoring by senior investigators and successful applicants will receive priority usage of the other cores in addition to the research funds.
Over 60% of world’s HIV-1 infected individuals are in sub-Saharan African nations. In particular Zambia has one of the highest rates of infection. As in many developing countries, the academic medical community in Zambia is not enviable, and due to limited funds, meaning the emphasis in training most often focuses on clinical medicine rather than on biomedical research. Consequently, little is done to significantly improve patient care and laboratory support services.
Faculty at the University of Zambia’s School of Medicine (UNZA) and the University Teaching Hospital (UTH), located in the country’s capital of Lusaka, recognize that to address the problem in rising cases of AIDS-associated diseases, including AIDS associated mental disorders and neurological diseases, a common and coordinated training and research program in NeuroAIDS is needed. Without such a program, it will be extremely difficult to develop the research capacity and infrastructure necessary to truly impact the country’s healthcare agenda and to position faculty to compete for future research funding so that they can fully and efficiently participate in future research initiatives in HIV-associate neurological diseases. In recognition of this, this International Core is as a new core for the CHAIN Center, where we will work with our colleagues in Zambia to address these important issues.
In order to support the goals of the CHAIN Center and its investigators, advanced mass spectrometric based analyses are needed. The aims proposed in the CHAIN Center cover a broad range of critical topics including
- biomarker discovery
- assessment of the role of macrophages in neuronal damage, and
- the need for CNS penetrating antiviral drugs.
These investigations are planned in order to advance our knowledge, prevention and treatment of neuroAIDS in the now chronic setting of HIV infection, and its relationship to aging.
The Phenomics Core will provide state of the art proteomic and metabolomics technologies to enable the identification, quantification, and correlation of the broad range of proteins and metabolites relevant to neuroAIDS.
Meeting this challenge is integral to understanding the now altered progression of disease and the development of diagnostic and treatment tools. Our methods and analyses will permit the identification of specific proteins and metabolites associated with neuroAIDS and its models.
One of expectations is that results of proteomics experiments will be integrated with metabolomics data. Through the use of analysis tools in this core, the Bioinformatics subunit of the Administrative Core and the Systems Biology Core, a collaborative effort will result in integrated data collection, sharing and analysis capabilities that are simultaneously integrated, not only enabling our investigators to meet their scientific aims but generating a unique resource for neuroAIDS. This will be accomplished within the core and CHAIN center as a whole and is directly applicable to in vitro, in vivo and ex vivo clinical translational studies performed in the examination of the effects of HIV on the CNS.
The Specific Aims are designed to meet the Center’s Action Plan, and the two core directors not only bring significant expertise in proteomics and metabolomics but also have a good understanding of HIV and its neurobiology, and experience in neuroAIDS studies, which facilitate the likelihood of success of CHAIN Center investigators.
Analytical instrumentation and scientific capabilities are complementary among proteomics and metabolomics components of this core. Both directors will promote and facilitate communication between the CHAIN Center investigators and the cores to insure that the most optimal experimental approaches and instrumentation will be used.
At its best, Systems Biology tightly couples experimental biology with modeling methodologies. Experimental data keep the theories generated through computation realistic; carefully constructed mathematical models can generate new testable hypotheses.
Achieving this balance, however, demands interdisciplinary collaborations as set up in the CHAIN Center, and the experience and skills as available in this core. The Systems Biology and Integrative Networks Core (SB-INC, aka Systems Biology Core) enables genome-scale technology and state-of-the-art bioinformatic tools for the study of neuroAIDS. CHAIN researchers can collect or analyze genome-scale data though active collaboration with members of the SB-INC.
Available experimental platforms include RNA-seq, chIP-seq, and protein interaction screens via Y2H and M2H.
Available bioinformatic technologies include clustering and classification of gene expression or metabolomic profiles, integration of molecular profiles with molecular networks, and identification of network-based biomarkers.
SB-INC will also support research and development centered on combinatorial transcriptional interaction maps. We will map the transcriptional networks underlying developmental processes of high relevance to neuroAIDS, including neuronal degeneration and protection and activation and differentiation of macrophages. Through these methods, we will develop network-based biomarkers to predict the potential for development of neuroAIDS, the presence of neuroAIDS, and response to treatment.
The goals of the Therapeutics Core are to provide nanoformulations to investigators pursuing nanoformulated antiretroviral and neuroprotective therapies for increased central nervous system (CNS) penetrance. The formulations developed address how monocytes and other immune cells may be harnessed for drug delivery.
Before such novel therapies can be administered to people, we will determine, in well-validated laboratory and animal models, the optimal doses and formulation administration. The crux of the problem facing the core, namely can nanoformulated antiretroviral therapy show sustained antiretroviral responses and slow release of drug in tissues, has now been addressed.
The core addresses a specific and important issue in the treatment of HIV and neuroAIDS, with broader implications for therapeutic interventions to other neurodegenerative diseases. Through this project, we will identify and manufacture candidate nanoformulations of currently used efficacious antiretrovirals. These will be tested in model systems of human disease, ranging from cultured monocytes to mice to monkeys, to examine pharmacokinetic, safety and efficacy. This core, overall, represents work that may prove to be a major advance in the development of long-lasting therapeutic agents that can lead to real treatments both systemic and CNS human disease.