A5045959300- Neuroinflammation and Neurodegeneration Mechanisms
- Single-cell and spatial transcriptomics
- Bioinformatics and Genomic Networks
- Glioma Diagnosis and Treatment
- Epigenetics and DNA Methylation
- Alzheimer's disease research and treatments
- Immune cells in cancer
- Cancer-related molecular mechanisms research
- MicroRNA in disease regulation
- Histone Deacetylase Inhibitors Research
- Ferroptosis and cancer prognosis
- Dementia and Cognitive Impairment Research
- Intracerebral and Subarachnoid Hemorrhage Research
- Atherosclerosis and Cardiovascular Diseases
- Nuclear Receptors and Signaling
- Protein Degradation and Inhibitors
- 14-3-3 protein interactions
- Genetic Associations and Epidemiology
- Acute Ischemic Stroke Management
- Tryptophan and brain disorders
- Stroke Rehabilitation and Recovery
- Barrier Structure and Function Studies
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Neurological Disease Mechanisms and Treatments
- Gene expression and cancer classification
University of Cincinnati Medical Center
2021-2025
Mayo Clinic in Florida
2019-2024
WinnMed
2019-2023
University of Cincinnati
2022
Jacksonville College
2022
Abstract Selective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable Alzheimer’s disease (AD), however the degree involvement differs among patients. We classified corticolimbic patterns neurofibrillary tangles postmortem tissue to capture extreme representative phenotypes. combined bulk RNA sequencing with digital pathology examine hippocampal AD. identified gene expression changes associated used...
Abstract To uncover molecular changes underlying blood-brain-barrier dysfunction in Alzheimer’s disease, we performed single nucleus RNA sequencing 24 disease and control brains focused on vascular astrocyte clusters as main cell types of gliovascular-unit. The majority the transcriptional were pericytes. Of targets predicted to interact with astrocytic ligands, SMAD3 , upregulated pericytes, has highest number ligands including VEGFA downregulated astrocytes. We validated these findings...
Large-scale brain bulk-RNAseq studies identified molecular pathways implicated in Alzheimer's disease (AD), however these findings can be confounded by cellular composition changes bulk-tissue. To identify cell intrinsic gene expression alterations of individual types, we designed a bioinformatics pipeline and analyzed three AD control datasets temporal dorsolateral prefrontal cortex from 685 samples. We detected cell-proportion brains that are robustly replicable across the independently...
Abstract Ischemic stroke, which accounts for 87% of cerebrovascular accidents, is responsible massive global burden both in terms economic cost and personal hardship. Many stroke survivors face long-term disability—a phenotype associated with an increasing number genetic variants. While clinical variables such as severity greatly impact recovery, polymorphisms linked to functional outcome may offer physicians a unique opportunity deliver personalized care based on their patient’s makeup,...
The aim of this study was to determine if plasma concentrations 5 surrogate markers Alzheimer's disease (AD) pathology and neuroinflammation are associated with status in African Americans.We evaluated 321 Americans (159 AD, 162 controls) from the Florida Consortium for African-American Disease Studies (FCA3DS). Five proteins reflecting AD neuropathology or inflammation (Aβ42, tau, IL6, IL10, TNFα) were tested associations age, sex, APOE MAPT genotypes, pairwise correlations.Plasma tau...
Introduction Glioblastomas utilize malignant gene expression pathways to drive growth. Many of these are not directly accessible with molecularly targeted pharmacological agents. Chromatin-modifying compounds can alter and target glioblastoma growth pathways. In this study, we a systematic screen chromatin-modifying on panel patient-derived lines identify promising their associated targets. Methods Five cell were subjected drug 106 representing 36 unique classes determine the twelve most...
Abstract Cerebral amyloid angiopathy (CAA) contributes to accelerated cognitive decline in Alzheimer’s disease (AD) dementia and is a common finding at autopsy. The APOE ε4 allele male sex have previously been reported associate with increased CAA AD. To inform biomarker therapeutic target discovery, we aimed identify additional genetic risk factors biological pathways involved this vascular component of AD etiology. We present genome-wide association study pathology cases report sex-...
Abstract Low-grade and secondary high-grade gliomas frequently contain mutations in the IDH1 or IDH2 metabolic enzymes that are hypothesized to drive tumorigenesis by inhibiting many of chromatin-regulating regulate DNA structure. Histone deacetylase inhibitors promising anti-cancer agents have already been used clinical trials. However, a clear understanding their mechanism gene targets is lacking. In this study, authors genetically dissect patient-derived mutant cultures determine which...
Abstract The pathological changes in epigenetics and gene regulation that accompany the progression of low-grade to high-grade gliomas are under-studied. authors use a large set paired atac-seq RNA-seq data from surgically resected glioma specimens infer regulatory relationships glioma. Thirty-eight patient samples underwent sequencing 16 additional analysis. Using an atac-seq/RNA-seq correlation matrix, peaks were with genes based on high values (|r 2 | > 0.6). Samples clustered by IDH1...
Abstract Blood-brain barrier (BBB) dysfunction is well-known in Alzheimer’s disease (AD), but the precise molecular changes contributing to its pathophysiology are unclear. To understand transcriptional brain vascular cells, we performed single nucleus RNA sequencing (snRNAseq) of temporal cortex tissue 24 AD and control brains resulting 79,751 nuclei, 4,604 which formed three distinct clusters characterized as activated pericytes, endothelia resting pericytes. We identified differentially...
Abstract Large-scale brain bulk-RNAseq studies identified molecular pathways implicated in Alzheimer’s disease (AD), however these findings can be confounded by cellular composition changes bulk-tissue. To identify cell intrinsic gene expression alterations of individual types, we designed a bioinformatics pipeline and analyzed three AD control datasets temporal dorsolateral prefrontal cortex from 685 samples. We detected cell-proportion brains that are robustly replicable across the...
Summary Selective vulnerability is a central concept to the myriad of devastating neurodegenerative disorders. Although hippocampus and cortex are selectively vulnerable in Alzheimer’s disease (AD), degree involvement lies along spectrum that we previously defined as AD subtypes revealing distinct clinical correlates. To operationalize heterogeneity spectrum, classified corticolimbic patterns neurofibrillary tangles capture extreme representative phenotypes. We combined bulk RNA sequencing...
Abstract Introduction Glioblastomas utilize malignant gene expression pathways to drive growth. Many of these are not directly accessible with molecularly targeted pharmacological agents. Chromatin-modifying compounds can alter and target glioblastoma growth pathways. In this study, we a systematic screen chromatin-modifying on panel patient-derived lines identify promising their associated targets. Methods Five cell were subjected drug 106 representing 36 unique classes determine the twelve...
Bulk tissue transcriptome studies can identify expression changes associated with pathology, however bulk represents a heterogeneous mix of cells and the proportion vary between samples by diagnosis. It is imperative to account for cell in such studies, which typically rely on type marker genes samples. Isolation sorted populations characterize profiles CNS types improve knowledge genes. We aim isolate from fresh surgical greater numbers older assess profile context sex APOE genotype,...
Alzheimer's disease is pathologically defined by the presence of extracellular amyloid beta plaques and intracellular tau tangles, resulting in neurodegeneration reactive gliosis affected brain regions such as temporal cortex (TCX). The degree distribution AD pathology can be Braak stage (tau) Thal phase (amyloid). Brain tissue comprised multiple cell types that have different molecular profiles, proportions which vary between individuals response to disease; creating challenges for...
Abstract Background Inter‐cellular communication within the gliovascular unit (GVU) is critical for cerebral blood flow regulation, and maintenance of blood‐brain‐barrier (BBB) properties. The breakdown BBB in Alzheimer’s disease (AD) well‐established, but precise underlying molecular changes remain unclear. Additionally, whether GVU alterations observed AD brains are also detected from living patients unknown. Further, these perturbations require further investigation different model...
Abstract Background Neurodegenerative disorders affect different brain regions at time points and to varying degrees, although the underlying reasons for this variability in regional susceptibility is unknown. Brain have proportions of cell types. This proportion may be further influenced by presence degree disorders, including neurodegenerative diseases. We postulate that genetic other factors influence type also provide insights into Methods Utilizing bulk transcriptomics data from 7...
Abstract Introduction: The pathological changes in epigenetics and gene regulation that accompany the progression of low-grade to high-grade gliomas are under-studied. authors use a large set paired atac-seq RNA-seq data from surgically resected glioma specimens infer regulatory relationships glioma.Methods: Thirty-eight patient samples underwent sequencing sixteen additional analysis. Using an atac-seq/RNA-seq correlation matrix, peaks were with genes based on high values (|r 2 |>0.6)....
Abstract Introduction: Low-grade and secondary high-grade gliomas frequently contain a mutation in the IDH1 metabolic enzyme that is hypothesized to drive tumorigenesis by inhibiting many of chromatin-regulating enzymes regulate DNA structure. Much previous research has focused on methylation leaving histone modifications relatively under-studied. Histone deacetylase inhibitors are promising anti-cancer agents have already been used clinical trials, however clear understanding their...
Abstract Background Inter‐cellular communication within the gliovascular unit (GVU) is critical for cerebral blood flow regulation, maintenance of blood‐brain‐barrier (BBB) properties, and brain energy metabolism. Although numerous cell biology studies demonstrate role GVU BBB breakdown in Alzheimer’s disease (AD), precise molecular changes contributing to its pathophysiology are unclear. Method We performed single nucleus RNA sequencing (snRNAseq) temporal cortex tissue 24 AD control brains...
Abstract Microglia have fundamental roles in health and disease, however effects of age, sex genetic factors on human microglia not been fully explored. We applied bulk single cell approaches to comprehensively characterize transcriptomes their associations with APOE . identified a novel microglial signature, characterized its expression data from 1,306 brain samples across 6 regions transcriptome. discovered co-expression network modules associated -ε4 that are enriched for lipid...
Abstract Introduction: The pathological changes in epigenetics and gene regulation that accompany the progression of low-grade to high-grade gliomas are under-studied. authors use a large set paired atac-seq RNA-seq data from surgically resected glioma specimens infer regulatory relationships glioma.Methods: Thirty-eight patient samples underwent sequencing sixteen additional analysis. Using an atac-seq/RNA-seq correlation matrix, peaks were with genes based on high values (|r 2 |>0.6)....