Biology subjects

Umfress, A.

Publications and source records attributed to Umfress, A..

3 recordsLinked to original sources

bioRxiv2026

GPCRs as Targets for Human Brain Modulation: A Multi-omic Atlas of Cell-Type Specific Expression

G Protein coupled receptors (GPCRs) are the largest class of clinically validated drug targets with nearly 35% of all approved therapeutic agents acting on these receptors. To further explore the potential of this class of receptors for the development of circuit-specific and mechanism-based therapeutic strategies for neurological disorders, we focused on GPCRs with no known endogenous ligand, orphan GPCRs (oGPCRs), because knowledge of their functions in the human brain remains rudimentary. Here, we utilized fluorescence activated nuclear sorting and sequencing (FANSseq) to generate deep molecular profiles of cell type specific nuclei isolated from post-mortem brains to generate an atlas of oGPCR expression across multiple regions of the human brain. We identified 22 oGPCRs that displayed selective cell-type enrichment both in RNA transcript expression and chromatin accessibility. We further validated each of these targets for cell-type specific expression in human brains and developed an open-source web atlas of all oGPCR expression in the human brain to serve as a neuro-resource for the broader scientific community. These studies reveal novel cell-type specific expression patterns of several oGPCRs, suggest potential endogenous roles for these receptors, and identify validated candidates for cell-type specific neuromodulation of the human brain. One Sentence SummaryThis study presents an atlas of orphan GPCR expression across the human brain for translational targeting.

neuroscience↗

bioRxiv2022

Characterization and Preclinical Treatment of Rotational Force-Induced Brain Injury

Millions of traumatic brain injuries (TBIs) occur annually. TBIs commonly result from falls, traffic accidents, and sports-related injuries, all of which involve rotational acceleration/deceleration of the brain. During these injuries, the brain endures a multitude of primary insults including compression of brain tissue, damaged vasculature, and diffuse axonal injury. All of these deleterious effects can contribute to secondary brain ischemia, cellular death, and neuroinflammation that progress for weeks to months after injury and impede neurological recovery. While the linear effects of head trauma have been extensively modeled, less is known about how rotational injuries mediate neuronal damage following injury. Here, we developed a new model of rotational head trauma in rodents and extensively characterized the pathological, behavioral, and electrophysiological effects of rotational TBI (rTBI). We identify aberrant cyclin dependent kinase 5 (Cdk5) activity as a principal mediator of rTBI and show pharmacological inhibition of Cdk5 reduces the cognitive and pathological consequences of injury. Finally, we utilize Cdk5-enriched phosphoproteomics to uncover potential downstream mediators of rTBI. These studies contribute meaningfully to our understanding of the mechanisms of rTBI and how they may be effectively treated.

neuroscience↗

bioRxiv2021

RORγt-Expressing Pathogenic CD4+T Cells Cause Brain Inflammation During Chronic Colitis

Neurobehavioral disorders and brain abnormalities have been extensively reported in both Crohns Disease (CD) and Ulcerative Colitis (UC) patients. However, the mechanism causing neuropathological disorders in inflammatory bowel disease (IBD) patients remains unknown. Studies have linked the Th17 subset of CD4+T cells to brain diseases associated with neuroinflammation and cognitive impairment, including multiple sclerosis (MS), ischemic brain injury and Alzheimers disease. To better understand how CD4+T lymphocytes, contribute to brain pathology in chronic intestinal inflammation, we investigated the development of brain inflammation in the T cell transfer model of chronic colitis. Our findings demonstrate that CD4+T cells infiltrate the brain of colitic Rag1-/- mice in proportional levels to colitis severity. Colitic mice developed hypothalamic astrogliosis that correlated with neurobehavioral disorders. Moreover, the brain-infiltrating CD4+T cells expressed Th17 cell transcription factor ROR{gamma}t and displayed a pathogenic Th17 cellular phenotype similar to colonic Th17 cells. Adoptive transfer of ROR{gamma}t-deficient naive CD4+T cells failed to cause brain inflammation and neurobehavioral disorders in Rag1-/- recipients, with significantly less brain infiltration of CD4+T cells. These findings suggest that pathogenic ROR{gamma}t+CD4+T cells that aggravate colitis migrate preferentially into the brain, contributing to brain inflammation and neurobehavioral disorders, thereby linking colitis severity to neuroinflammation.

immunology↗