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The principles in our lab are shaped around the premise that biological responses of astrocytes and microglia to neurodegenerative diseases aren’t neatly categorized into binary relationships. Rather, the responses of these critical cell populations are shaped by a continuum of factors driving aging and/or disease-related heterogeneity. Importantly, deciphering the heterogeneity and susceptibility of these cell populations may provide exciting clues as to the mechanisms underlying brain dysfunction. Approaches in the lab are geared around applying multidisciplinary approaches to study the complex heterogeneous inflammatory response of astrocytes and microglia across a variety of neurodegenerative disease models. Cutting-edge technologies using single-cell RNA sequencing (scRNAseq), spatial transcriptomics, fluorescently activated cell sorting (FACS), cell-specific conditional knockout (cKO) models, and bioinformatics are just some of the resources at our disposal to answer our questions.


Aging and TBI

Traumatic brain injury (TBI) is significantly correlated with increased risk for developing several neurodegenerative disorders, including Alzheimer’s Disease related dementia (ADRD). Compounding these correlates is that aging is a substantial factor in the incidence and vulnerability to TBI. Owing to the complexities surrounding TBI as a progressive neurodegenerative disorder leading to AD/ADRD, the cellular mechanisms potentially underlying the aging brain’s susceptibility to acquire degenerative responses remains elusive. Our current interests are focused on unraveling how and why the aged brain has dysfunctional neuroinflammatory responses to TBI, and whether targeting specific inflammatory transcription factors in astrocytes and microglia may offer sparing of chronic neurodegenerative sequelae.

Figure: Aging-associated clasmatodendritic astrocytes (Early et al., 2020). 

Cerebral Amyloid Angiopathy

Vascular Cognitive Impairment Dementia

Cerebrovascular disease is increasingly recognized as a critical factor driving dementia. VCID is an umbrella term for a variety of types of dementia believed to stem from vascular dysfunction/disease(s). Multiple lines of evidence in both humans as well as animal models suggest that altered astrocyte function in response to cerebrovascular dysfunction plays a critical role with the initiation and progression of VCID and Alzheimer's disease (AD), potentially suggesting convergent pathophysiological mechanisms. Our research interests in this space lie with determining how inflammatory signaling between astrocytes, vasculature, and microglia underlie both the initiation and progression of degenerative sequelae in VCID as well as comorbid VCID/AD. Projects in this area capitalize on both novel rodent models as well as the Sanders-Brown/UKY ADC tissue bank.

Figure: Cortical infarct from transient tandem stroke (Red = Gfap, Blue = X34 Amyloid)

APOE Immunometabolism

Polymorphisms in APOE is one the the strongest genetic risk factors for sporadic Alzheimer's disease, particular the E4 allele that is associated with an almost 16 times higher risk, compared to homozygous E3 carriers. Compounding matters, E4 carriers have been consistently documented to have worsened outcomes following TBI. In collaboration with the Johnson Lab and Sun Lab at UK, we are exploring how APOE and its polymorphisms alter immunometabolic functions of astrocytes and microglia exposed to TBI using novel cell-specific rodent models as well as leveraging post-mortem brain tissue of individuals with a history of TBI from the Sanders-Brown/UKY ADC tissue bank.

Figure: Hippocampal microglia reactivity following TBI in our mouse model


We are very fortunate to have generous support for our research endeavors, please check out NIH RePORTER for a synopsis of our current Federal funding. 

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