Biomedical Graduate Studies

Description of Research Expertise

Research Interests
-Assessing intra and inter-cellular signaling in neurons and oligodendrocyte responding to astrocyte and microglial activation due to various neuroinflammatory stimuli (i.e. HIV infection oxidative stress, chemokines/cytokines, excitotoxicity).
-Determining mechanisms of neuroprotection in neuroinflammatory insult.
-Molecular mechanisms underlying neuronal loss in neurodegenerative disorders (i.e. Alzheimer’s Disease, Parkinson’s disease, and HIV associated neurocognitive disorders). We are specifically interested in organellar stress and communication between the endoplasmic reticulum and lysosome as well as the endogenous antioxidant response in neurons and oligodendrocytes.

Key words: Endoplasmic Reticulum Stress Response, PERK, Integrated Stress Response, Lysosome, Organellar stress, Neurodegeneration, Transcription, Primary Culture, HIV associated Neurocognitive Disorder, HIV encephalitis, Alzheimer Disease, Cell Cycle, Oxidative Stress Response, Antioxidant Response, Cannabinoids, neuroinflammation. Antiretrovirals, oligodendrocytes, microglia, astrocytes, .

Description of Research
Our laboratory investigates the intra- and inter-cellular signaling that occurs during neuroinflammation in the CNS, with a particular focus on changes in people with HIV, Alzheimer Disease and Parkinson Disease. We are examining the impact of microglial and astrocyte activation on cell signaling and organellar stress in neurons and oligodendrocytes in response to stimuli associated with these chronic degenerative disorders. We are also interested in therapeutic approaches to regulate these interactions including those that target lysosomal and endoplasmic reticulum function and inflammation.

While People with HIV associated Brain injury, AD, and PD exhibit different pathologic features, theories as to their etiology share common molecular mechanisms including changes in the neuroinflammatory environment, organellar stress, oxidative stress. We hypothesize that neurons and oligodendroctyes respond to these neurodegenerative stimuli by activating organellar stress responses resulting in an integrated attempt to restore homeostasis at the cellular level; however, the organellar stress response has cell type specific features that are distinct between the cells of the CNS: neurons, oligodendrocytes, astrocytes and microglia. We are examining how the stress pathways disrupted in HIV associated Brain injury as well as degenerative diseases like Alzheimer disease differ between cells of the CNS and how they can be therapeutically leveraged to modify disease progression.

Our studies and others have shown a contributory role of the unfolded protein response (UPR) in people with HIV and in the context of cognitive impairment. We have become particularly interested in the Protein Kinase R-like endplasmic reticulum kinase (PERK), and its response to neuroinflammatory stimuli in neurons and oligodendrocytes or how it is induced in neuroinflammatory cells such as astrocytes and microglia. PERK has several genetic variants that range from common to rare, with some of the rare changes being associated with Walcott-Rallison syndrome and Alzheimer disease. Minor PERK variants have been associated with mild to moderate risk for progressive supranuclear palsy, diabetes, Alzheimer disease and lung cancer. We have found an association between PERK genetic variants and cognitive deficit's in people with HIV. Our lab is interested in investigating how these genetic variants increase risk for cognitive, behavioral and motor outcomes in people with HIV. Using biochemical, molecular and cellular approaches we are studying the impact of these genetic variants on PERK expression and function. We are also interrogating the impact of these variants in both animal models and human induced pluripotent stem cell models with the goal of understanding how these variants increase risk for disorders of the CNS and pancreas.

A second area of research in our laboratory is the study of the endogenous anti-oxidant response and its failure to prevent accumulation of oxidative damage and neuronal loss in neurodegenerative disorders. The two proteins of direct interest to the laboratory are Keap1 and Nrf2. Nrf2 is a transcription factor that regulates the expression of the enzymes responsible for the antioxidant response. Normally, Nrf2 is bound in the cytoplasm by the Kelch ECH associated protein 1(Keap1). However, in response to oxidative stress, sulfhydryl groups on Keap1 become oxidized releasing Nrf2 for translocation into the nucleus. We have reported that Nrf2 is aberrantly expressed in AD indicating it is not responding to oxidative stress in neurons of affected brain regions. Interestingly, Nrf2 does appear to be responding appropriately in neurons affected in PD. This has led us to hypothesize that the endogenous antioxidant response is aberrant in AD, but insufficient in PD. Our current studies focus on identifying differences in regulation of the endogenous antioxidant response in AD and PD. The goal of these studies is to explore this pathway as a therapeutic target for neurodegenerative conditions. By enhancing the endogenous anti-oxidant response, neuronal toxicity may decrease leading to increased neuronal function in these patients.

By assessing the interaction of these convergent pathways and organellar signaling in cells of the CNS responding to neurodegenerative stimuli such as oxidative damage, misfolded proteins, and inflammation, we hope to gain a greater understanding of the basic mechanisms underlying neuronal damage, dysfunction and loss in neurodegenerative diseases and identify drugable targets for treatment of AD, PD, and HIV associated Brain injury.

Rotation Projects
1. Investigation of PERK Genetic variants on HIV induced brain injury and Alzheimer-related insults

2. Understanding the role of copper metabolism on PERK kinase function and endoplasmic reticulum and lysosomal stress.

3. Role of cannabinoids in modulating HIV replication, neuroinflammation and neuronal function in human induced pluripotent stem cell models and 3-D cerebral organoids.

4. Mechanisms of HIV antiretroviral drug-induced changes in oligodendrocyte differentiation and myelination

5. Role of organellar stress on stress granule formation and lipid synthesis in differentiating oligodendrocytes

6. understanding unique impact of HIV and antiretroviral drugs on the developing CNS, particularly white matter.

7. Methods to quantify the characteristics of the HIV reservoir in cells of the CNS from pro-viral integration to transcriptomic changes





Lab personnel:
Çagla Akay Espinoza, M.D., Research Assistant Professor
Lindsay Festa, Ph.D., Research Associate
Elena Alvarez Periel, Ph.D., Research Associate
Serguei Spitsin, Ph.D., Research Specialist
Xinglong Shi, M.S., Lab Manager
Jitendra, Arya, Ph.D., Postdoctoral Fellow
Celia Cui, Ph.D., Postdoctoral Fellow
Marisa Jefferies, Ph.D., Postdoctoral Fellow
Caela Long, B.S., Graduate Student, Neuroscience Graduate Group
James Gesualdi, B.S., Graduate Student, Cell and Molecular Biology, Microbiology, Virology and Parasitology Program
Eliana von Krusenstiern, B.S. Graduate Student, Pharmacology Graduate Group
Johnathan Wong, B.S., Graduate Student, Pharmacology Graduate Group
Angela Bongiovanni, B.S., Graduate Student, Neuroscience Graduate Group
Gabriela Colon Roura, B.S., Graduate Student, Pharmacology Graduate Group
Teshawn Johnson, B.S. Graduate Student, Cell and Molecular Biology, Development, Stem Cell and Regenerative Biology Program