Biology subjects

Bibb, J. A.

Publications and source records attributed to Bibb, J. A..

6 recordsLinked to original sources

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↗

bioRxiv2022

Genetic Impairment of Succinate Metabolism Disrupts Bioenergetic Sensing in Adrenal Neuroendocrine Tumor

Metabolic dysfunction mutations can impair energy sensing and cause cancer. Loss of function of mitochondrial TCA cycle enzyme, succinate dehydrogenase B (SDHB) results in various forms of cancer typified by pheochromocytoma (PC). Here we delineate a signaling cascade where the loss of SDHB induces the Warburg effect in PC tumors, triggers dysregulation of Ca2+ homeostasis, and aberrantly activates calpain and the protein kinase Cdk5, through conversion of its cofactor from p35 to p25. Consequently, aberrant Cdk5 initiates a cascade of phospho- signaling where GSK3 inhibition inactivates energy sensing by AMP-kinase through dephosphorylation of the AMP-kinase {gamma} subunit, PRKAG2. Overexpression of p25-GFP in mouse adrenal chromaffin cells also elicits this phosphorylation signaling and causes PC tumor formation. A novel Cdk5 inhibitor, MRT3-007, reversed this phospho-cascade, invoking an anti- Warburg effect, cell cycle arrest, and senescence-like phenotype. This therapeutic approach halted tumor progression in vivo. Thus, we reveal an important novel mechanistic feature of metabolic sensing and demonstrate that its dysregulation underlies tumor progression in PC and likely other cancers. HighlightsO_LILoss of SDHB function in pheochromocytoma causes Ca2+ dysregulation, calpain activation, and aberrant activation of the protein kinase Cdk5. C_LIO_LIHyperactive Cdk5 deregulates a GSK3/PRKAG2/AMPK signaling cascade. C_LIO_LIp25 overexpression and consequent aberrant Cdk5 activity in chromaffin cells causes pheochromocytoma. C_LIO_LIInhibition of Cdk5 activates the PRKAG2/AMPK/p53 signaling to rescue cell senescence and block PC tumor progression. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=175 SRC="FIGDIR/small/475410v2_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@16f0a48org.highwire.dtl.DTLVardef@10c1c7aorg.highwire.dtl.DTLVardef@21b100org.highwire.dtl.DTLVardef@1eb8674_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Integrated Regulation of PKA by Fast and Slow Neurotransmission in the Nucleus Accumbens Controls Plasticity and Stress Responses

Cortical glutamate and midbrain dopamine neurotransmission converge to mediate striatum-dependent behaviors, while maladaptations in striatal circuitry contribute to mental disorders. Here we uncover a molecular mechanism by which glutamatergic and dopaminergic signaling integrate to regulate cAMP-dependent protein kinase (PKA) via phosphorylation of the PKA regulatory subunit, RII{beta}. We find that glutamate-dependent reduction in Cdk5-dependent RII{beta} phosphorylation alters the PKA holoenzyme auto-inhibitory state to increase PKA signaling in response to dopamine. Disruption of RII{beta} phosphorylation by Cdk5, consequently, enhances cortico-ventral striatal synaptic plasticity. Acute and chronic stress in rats inversely modulate RII{beta} phosphorylation and ventral striatal infusion of a small interfering peptide that selectively targets RII{beta} regulation by Cdk5 improves behavioral response to stress. This new signaling mechanism integrating ventral striatal glutamate and dopamine neurotransmission is likely important to brain function, may contribute to neuropsychiatric conditions, and serves as a possible target for the development of novel therapeutics for stress-related disorders.

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↗

bioRxiv2019

Novel anti-somatostatin receptor 2 antibody-drug conjugate for neuroendocrine cancer therapy

Neuroendocrine (NE) cancers include a diverse spectrum of hormone-secreting neoplasms that arise from the endocrine and nervous systems. Current chemo- and radio- therapies have marginal curative benefits. This study aimed to develop an innovative antibody-drug conjugate (ADC) to effectively treat NE tumors (NETs). We first confirmed that somatostatin receptor 2 (SSTR2) is an ideal surface target by analyzing 38 patient-derived NET tissues, 33 normal organs, and 3 NET cell lines. We then developed a new monoclonal antibody (mAb, IgG1 and kappa) to target two extracellular domains of SSTR2, which showed strong and specific surface binding to NETs. The ADC was constructed by conjugating the anti-SSTR2 mAb and antimitotic monomethyl auristatin E. In vitro evaluations indicated that the ADC can effectively bind, internalize, release payload, and kill NET cells effectively. Finally, the ADC was evaluated in vivo using a NET xenografted mouse model to determine cancer targeting, maximal tolerated dosage, pharmacokinetics, and anti-cancer efficacy. The anti-SSTR2 ADC was able to exclusively target and kill NETs with minimal toxicity and high stability in vivo. This study demonstrates that the anti-SSTR2 mAb-based ADC has high therapeutic values for NET therapy.

bioengineering↗

bioRxiv2019

Phosphoprotein-based Biomarkers as Predictors for Cancer Therapy

Disparities in cancer patient responses have prompted widespread searches to identify differences in sensitive vs. non-sensitive populations and form the basis of personalized medicine. This customized approach is dependent upon the development of pathway-specific therapeutics in conjunction with biomarkers that predict patient responses. Here, we show that Cdk5 drives growth in subgroups of human patients with multiple types of neuroendocrine neoplasms. Phosphoproteomics and high throughput screening identified novel phosphorylation sites downstream of Cdk5. These phosphorylation events serve as biomarkers of Cdk5 activity and effectively pinpoint Cdk5-driven tumors. Toward achieving targeted therapy, we demonstrate that mouse models of neuroendocrine cancer are responsive to selective Cdk5 inhibitors and biomimetic nanoparticles are effective vehicles for enhanced tumor targeting and reduction of drug toxicity. Finally, we show that biomarkers of Cdk5-dependent tumors effectively predict response to anti-Cdk5 therapy in patient-derived xenografts. Thus, a phosphoprotein-based diagnostic assay combined with Cdk5-targeted therapy is a rational treatment approach for neuroendocrine malignancies.

cancer biology↗