HIV Associated Neurocognitive Disorders
Dr. Haughey’s lab was the first group to demonstrate that alterations in brain sphingolipid metabolism are associated with cognitive impairment in HIV-infected patients. These early cross sectional studies were expanded to include longitudinal cerebral spinal fluid and serum/plasma samples from patients in cohort studies including the North Eastern AIDS Dementia (NEAD) Cohort, the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) group, a cohort of HIV-infected women in Puerto Rico and a cohort of HIV-infected Hawaiians. The findings from these studies have identified specific biochemical abnormalities in sphingolipid metabolism that are “prognostic” and “associative” indicators of changes in cognitive status. These biomarkers are beginning to elucidate disease mechanisms that suggest a deficit of endolysosmal function may contribute to neurodegeneration in HIV infected individuals. These biomarkers may ultimately be clinically useful to identify patients at risk for cognitive decline and currently are being tested as surrogate markers for neuroprotective therapeutics.
We have determined that the composition of lipids and sterols are altered during the remyelination process. Modeling the biophysical consequence of this modification in lipid composition suggests an increase in the repulsive force between opposing bilayers that could explain decompaction and disruption of myelin structure. Ongoing studies are elucidating the mechanisms for abnormal remyelination, and are testing a potential therapeutic approach developed in the Haughey group to regulate immune function through the modulation of sphingolipid metabolism in developing and mature oligodendroglia.
A biomarker is generally defined as a characteristic that is evaluated as an indicator of normal biologic processes, a pathogenic processes, or pharmacologic responses to a therapeutic intervention. Many neurodegenerative diseases have a prolonged prodromal period during which subtle changes in brain physiology occur. As these changes precede the onset of cognitive impairment, biomarkers to identify individuals at high risk for developing dementia at this stage could provide the opportunity for early intervention when therapeutics are likely to have the greatest benefit. In addition to these prognostic measures of brain health, biomarkers can also be used as surrogate measures that can be used in pre-clinical model systems, and clinical trials to more efficiently determine if a treatment or intervention produced the desired biological effect. We use state-of-the-art proteomic, lipidomic, and metabolomics technologies to identify biomarkers. These technologies are largely based on mass spectrometry, bioinformatics, computational, and statistical analyses of the resulting data. Diseases currently under study include HIV-Associated Neurocognitive Disorders
Other Dementias and Cognitive Aging
The lab has been involved with multiple biomarker studies with subjects at risk for Alzheimer’s (identified by familial linkages or advanced age) to identify surrogate markers that were prognostic for cognitive decline, and associative indicators for cognitive impairment. In each of these populations alterations in particular species of lipids were found to vary in relation to impairment. Moreover, a number of these metabolites were prognostic indicators for increased risk of AD. These studies have now been expanded into a cohort of more than 3000 subjects from the Baltimore Longitudinal Study on Aging to identify normal ranges for the metabolites in blood, and to validate these findings for ongoing biomarker development.
Discoveries obtained from clinical studies are often used to drive basic research. For example, the finding that certain forms of sphingomyelin and ceramide are increased in the brain and CSF from HIV infected patients with dementia has lead to discoveries of how focal changes in sphingolipid content are regulated to influence neural cell function. For example, the Haughey lab has shown that rapid and transient increases of long-chain sphingomyelins and ceramides modulate synaptic strength through regulation of NMDA receptor trafficking, while long-term changes that result in the accumulation of ceramide evokes death-pathways through alterations in receptor trafficking.
Extracellular Vesicle Biology and Physiology
In general, there are two types of extracellular vesicles (EVs) that can be released from cells in a regulated manner. Microvesicles are large complexes (150 to >200 nm diameter) formed by the outward budding and fission of the plasma membrane. Exosomes are smaller complexes (80 to 100 nm diameter) formed by the endocytosis of endosomal membranes that fuse with the plasma membrane to release exosomes. EVs bind, and are taken up by multiple types of cells where their cargo (that includes hundreds of different kinds of lipids, proteins, and RNA), regulate cellular functions. In the lab, we are actively studying the mechanisms by which EVs released from astrocytes regulate
Neuroinflammation and Neurodegenerative Disease
Chronic low-level inflammation (sometimes called a smoldering inflammation) and/or periodic neuroinflammatory events contribute to neuronal damage and cell death in a variety of neurodegenerative conditions. Unfortunately, brain inflammation has proven to been a difficult therapeutic target, and certain types of inflammation are protective, beneficial and instruct repair mechanisms in the CNS. We have several projects ongoing that are designed to better understand the beneficial vs degenerative aspects of the neuroinflammatory response in acute and chronic conditions (current focus is on acute phase response and complement systems) so that we can identify appropriate molecular targets for therapeutic development.