Student Research Fellowship Program
A mentored research program for our medical, dental and pharmacy students
Christine Crish, Ph.D.
Early neurotransmitter deficits are associated with non-cognitive risk factors in Alzheimer’s model mice
A major goal of our laboratory is to understand some of the earliest pathological mechanisms that contribute to Alzheimer’s brain pathology. Decades prior to the first signs of cognitive deficits, changes begin to occur in the brain that may be associated with deficits in sensory function, appetite, continence, and other fundamental processes known to predict increased risk for dementia. There is a critical need to identify and understand these early factors in order to develop early methods for detecting disease and potentially intervening.
Our lab has preliminary data showing alterations in populations of GABA and acetylcholine producing neurons in the brains of Alzheimer’s (AD) model mice that precede onset of disease. Our goal is to determine which specific subpopulations of these neurons are affected in specific regions of the hippocampus and cortex at early time points in order to identify brain circuits at greatest risk for damage. These brain circuits may involve visual system dysfunction, incontinence, or other metabolic disruptions which would enable us to establish mechanistic basis for some of these early risk indicators for dementia.
Takhar Kasumov, Ph.D. – 1
ACSS2 and Acetylation Remodeling in Alcohol-Induced Tauopathy.
Alzheimer’s disease (AD), the sixth leading cause of death in the United States, increases markedly with age. Chronic alcohol consumption accelerates brain aging and heightens AD risk by disrupting pathways essential for neuronal homeostasis1. Alcohol impairs brain energy metabolism and perturbs histone acetylation, critical regulators of proteostasis, synaptic plasticity, and memory formation2, 3. Alcohol use is also associated with increased tauopathy, yet the mechanistic link between alcohol-driven metabolic dysfunction and AD progression remains poorly defined.
Takhar Kasumov, Ph.D. – 2
Stable Isotope Tracing of Mitochondrial Proteins and mtDNA Dynamics in Alzheimer’s Tauopathy
Alzheimer’s disease (AD), the leading cause of dementia and a major global health challenge, is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss [1-3]. Pathologically, AD is marked by extracellular -amyloid accumulation and intracellular neurofibrillary tangles formed from tau aggregation [4]. Mitochondrial dysfunction is a central contributor to neurodegeneration in AD. Mitochondrial DNA (mtDNA), due to its limited repair capacity and proximity to reactive oxygen species production sites, is particularly susceptible to oxidative damage [5]. Several forms of pathogenic tau impair neuronal bioenergetics and may lead to disrupted mitochondrial dynamics (fusion and fission balance), and block mitophagy, preventing clearance of defective mitochondria [6]. Using our mass spectrometry platform, we demonstrated that differentially abundant proteins in tauopathy mouse brain are predominantly associated with tau aggregation and autophagy regulation, accompanied by impaired mitochondrial integrity and function.
Erin Reed, Ph.D. – 1
Characterization of innate lymphoid cells in a mouse model of Alzheimer’s disease
Alzheimer’s disease (AD) is the primary cause of dementia, characterized by robust inflammation within the brain that accompanies the pathological hallmarks of amyloid plaques and neurofibrillary tau tangles. Microglia, the resident innate immune cells of the brain, mediate this process, driving AD pathogenesis; however, they also signal to circulating peripheral immune cells to instruct their function and phenotype. These peripheral cells similarly contribute to the inflammatory environment of the AD brain, but how they contribute to disease processes remains unclear. We hypothesize innate lymphoid cells (ILCs) from the circulation localize at brain-border interfaces (meninges and choroid plexus) to modulate parenchymal AD pathology through their actions on B cells. We propose to determine the localization and composition of ILCs during disease onset and progression, their reliance on specific signaling pathways for their action, and their influence on B cells.
Erin Reed, Ph.D. – 2
Identifying novel regulatory mechanisms behind lymphocyte contributions to a mouse model of Alzheimer’s disease
Alzheimer’s disease (AD) is the primary cause of dementia, characterized by robust inflammation within the brain that accompanies the pathological hallmarks of amyloid plaques and neurofibrillary tau tangles. Microglia, the resident innate immune cells of the brain, mediate this process, driving AD pathogenesis; however, they also signal to circulating peripheral immune cells to instruct their function and phenotype. These peripheral cells similarly contribute to the inflammatory environment of the AD brain, but how they contribute to disease processes remains unclear. We hypothesize the sex chromosomes and gonadal hormones drive specific aspects of lymphocyte biology, biasing their phenotype and function to promote a detrimental inflammatory milieu for the onset and progression of pathology. We propose to determine the localization and phenotype of lymphocytes in the brain and meninges based on the complement of sex chromosomes and gonadal hormones.
Matthew Smith, Ph.D.
Metabolic and Structural Retinal Vulnerabilities Following Traumatic Brain Injury
Traumatic brain injury (TBI) frequently leads to lasting visual and circadian disturbances, implicating secondary neurodegeneration within retinal ganglion cells (RGCs) and their central projections. The retina offers a unique, accessible model to investigate neurodegenerative processes after TBI, as it mirrors central nervous system (CNS) pathology while allowing for precise visualization and molecular interrogation of axonal and synaptic alterations.
Xinwen Wang, Ph.D.
Impact of Catechol-O-Methyltransferase (COMT) Genetic Polymorphisms on the Effectiveness of COMT Inhibitors
Parkinson’s Disease (PD), the second most common neurodegenerative disorder worldwide, affects approximately 1% of individuals over age 60(Rizek, Kumar, & Jog, 2016). catechol-O-methyltransferase (COMT) inhibitors are widely used as adjunctive therapy to enhance levodopa therapy by blocking COMTmediated levodopa metabolism. However, patient responses to COMT inhibitors vary, a significant portion of the patients do not benefit from the combined therapy(Gray, et al., 2022). There is a critical clinical need to identify the factors may influence how effectively these drugs suppress COMT activity and thereby enhance levodopa activation. Single nucleotide polymorphisms (SNPs) within the COMT gene, particularly rs4633, rs4818, and rs4680, have been associated with poor response to levodopa therapy in PD patients (Lin, Fan, Lin, Chang, & Wu, 2018). Despite their high population frequencies, the molecular consequences of these variants and haplotypes on COMT inhibitor responsiveness remain poorly defined. This project aims to characterize how rs4633, rs4818, and rs4680 and their haplotypes influence COMT expression and activity, and consequently, the magnitude of COMT inhibitor–mediated enhancement of levodopa activation. Findings will provide crucial mechanistic insight to inform precision therapy in PD.
CONTACT
Nona Hose
Phone: 330.325.6499
Email: nhose@380cebbe0d.nxcli.io
These projects are funded by the Office of Research and Sponsored Programs (ORSP).