A5035741637- Protein Degradation and Inhibitors
- Cancer-related gene regulation
- Chromatin Remodeling and Cancer
- Genomics and Chromatin Dynamics
- Cancer Mechanisms and Therapy
- Alzheimer's disease research and treatments
- RNA modifications and cancer
- Ubiquitin and proteasome pathways
- Epigenetics and DNA Methylation
- Nerve injury and regeneration
- Neuroblastoma Research and Treatments
- interferon and immune responses
- Mechanisms of cancer metastasis
- Genetic Neurodegenerative Diseases
- Neuroscience and Neural Engineering
- Neurogenesis and neuroplasticity mechanisms
- Nuclear Receptors and Signaling
- Microtubule and mitosis dynamics
- Enzyme function and inhibition
- Prion Diseases and Protein Misfolding
- Polyamine Metabolism and Applications
- Endoplasmic Reticulum Stress and Disease
- Cancer Treatment and Pharmacology
- Down syndrome and intellectual disability research
- Cancer therapeutics and mechanisms
Middle Tennessee State University
2021-2025
Vanderbilt University
2015-2022
University of California, San Diego
2012-2016
Neurotrophic factors are best known for their roles in both development and continued maintenance of the nervous system. Their strong potential to elicit pro-survival pro-functional responses neurons peripheral central system make them good drug candidates treatment a multitude neurodegenerative disorders. However, significant obstacles remain need be overcome before translating neurotrophins into therapeutic arena. This article addresses current efforts advances resolving these challenges...
The endosome/lysosome pathway is disrupted early in the course of both Alzheimer's disease (AD) and Down syndrome (DS); however, it not clear how dysfunction this influences development these diseases. Herein, we explored cellular molecular mechanisms by which endosomal contributes to pathogenesis AD DS. We determined that full-length amyloid precursor protein (APP) its β-C-terminal fragment (β-CTF) act though increased activation Rab5 cause enlargement endosomes disrupt retrograde axonal...
The chromatin-associated protein WDR5 is a promising target for pharmacological inhibition in cancer. Drug discovery efforts center on the blockade of "WIN site" WDR5, well-defined pocket that amenable to small molecule inhibition. Various cancer contexts have been proposed be targets WIN site inhibitors, but lack understanding genes and primary effects inhibitors hampers their utility. Here, by potent we demonstrate links chromatin at cohort loci, including specific subset ribosome genes....
The oncoprotein transcription factor MYC is overexpressed in the majority of cancers. Key to its oncogenic activity ability regulate gene expression patterns that drive and maintain malignant state. also considered a validated anticancer target, but efforts pharmacologically inhibit have failed. dependence on cofactors creates opportunities for therapeutic intervention, any cofactor this requires structural understanding how interacts with MYC, knowledge role it plays function, demonstration...
The oncoprotein transcription factor MYC is a major driver of malignancy and highly validated but challenging target for the development anticancer therapies. Novel strategies to inhibit may come from understanding co-factors it uses drive pro-tumorigenic gene expression programs, providing their role in activity understood. Here we interrogate how one co-factor, host cell (HCF)–1, contributes human Burkitt lymphoma setting. We identify genes connected mitochondrial function ribosome...
SMARCB1 encodes the SNF5 subunit of SWI/SNF chromatin remodeler. also interacts with oncoprotein transcription factor MYC and is proposed to stimulate activity. The concept that a coactivator for MYC, however, at odds its role as tumor-suppressor, observations loss leads activation target genes. Here, we reexamine relationship between using biochemical genome-wide approaches. We show inhibits DNA-binding ability impedes gene recognition by in cells. further regulation separable from...
Abstract WDR5 is a highly-conserved nuclear protein that performs multiple scaffolding functions in the context of chromatin. also promising target for pharmacological inhibition cancer, with small molecule inhibitors an arginine-binding pocket (the ‘WIN’ site) showing efficacy against range cancer cell lines vitro. Efforts to understand WDR5, or establish mechanism action WIN site inhibitors, however, are stymied by its many nucleus, and lack knowledge conserved gene networks—if any—that...
The chromatin-associated protein WDR5 is a promising pharmacological target in cancer, with most drug discovery efforts directed against an arginine-binding cavity called the WIN site. Despite clear expectation that site inhibitors will alter repertoire of interaction partners, their impact on interactome remains unknown. Here, we use quantitative proteomics to delineate how changed by inhibition. We show inhibitor alters dozens proteins, including those linked phosphatidylinositol 3-kinase...
Abstract WDR5 nucleates the assembly of histone-modifying complexes and acts outside this context in a range chromatin-centric processes. is also prominent target for pharmacological inhibition cancer. Small-molecule degraders have been described, but most drug discovery efforts center on blocking WIN site WDR5, an arginine binding cavity that engages MLL/SET enzymes deposit histone H3 lysine 4 methylation (H3K4me). Therapeutic application inhibitors complicated by disparate functions...
Alzheimer's disease (AD) is a neurodegenerative pathologically characterized by amyloid plaques and neurofibrillary tangles in the brain. Before these hallmark features appear, signs of axonal transport defects develop, though initiating events are not clear. Enhanced amyloidogenic processing precursor protein (APP) plays an integral role AD pathogenesis, previous work suggests that both Aβ region C-terminal fragments (CTFs) APP can cause defects. However, it remains unknown if affects...
Clues to Alzheimer disease (AD) pathogenesis come from a variety of different sources including studies clinical and neuropathological features, biomarkers, genomics animal cellular models. An important role for amyloid precursor protein (APP) its processing has emerged considerable interest been directed at the hypothesis that Aβ peptides induce changes central pathogenesis. Accordingly, molecules reduce levels have discovered such as γ-secretase inhibitors (GSIs) modulators (GSMs). GSIs...
WDR5 is a component of multiple epigenetic regulatory complexes, including the mixed lineage leukemia (MLL)/SET complexes that deposit histone H3 lysine 4 methylation. Inhibitors an arginine-binding cavity in WDR5, known as WDR5-interaction (WIN) site, have been proposed to selectively kill MLL-rearranged malignancies via mechanism. We discovered potent WIN site inhibitors and found they MLL cancer cells not through changes methylation, but by displacing from chromatin at protein synthesis...
WD40 Repeat Domain 5 (WDR5) is a highly conserved nuclear protein that recruits MYC oncoprotein transcription factors to chromatin stimulate ribosomal gene expression. WDR5 tethered via an arginine-binding cavity known as the “WIN” site. Multiple pharmacological inhibitors of WDR5-interaction site (WINi) have been described, including those with picomolar affinity and oral bioavailability in mice. Thus far, however, WINi only shown be effective against number rare cancer types retaining...
BDNF plays an important role in several facets of neuronal survival, differentiation, and function. Structural functional deficits axons are increasingly viewed as early feature neurodegenerative diseases, including Alzheimer's disease (AD) Huntington's (HD). As yet unclear is the mechanism(s) by which axonal injury induced. We reported development a novel technique to produce biologically active, monobiotinylated (mBtBDNF) that can be used trace transport BDNF. Quantum dot-labeled (QD-BDNF)...
Abstract Rhabdoid tumors (RT) are rare and deadly pediatric cancers driven by loss of SMARCB1, which encodes the SNF5 component SWI/SNF chromatin remodeler. Loss SMARCB1 is associated with a complex set phenotypic changes including vulnerability to inhibitors protein synthesis p53 ubiquitin-ligase HDM2. Recently, we discovered small molecule ‘WIN’ site WDR5, in MLL-rearranged leukemia cells decrease expression genes linked synthesis, inducing translational choke causing p53-dependent...
The autotaxin–lysophosphatidic acid receptor (ATX-LPAR) signaling axis is pivotal in various clinical conditions, including cancer and autoimmune disorders. This promotes tumorigenicity by interacting with the tumor microenvironment, facilitating metastasis, conceding antitumor immunity, thereby fostering resistance to conventional therapies. Recent studies highlight promise of ATX/LPAR inhibitors combination chemotherapeutic drugs overcome some forms this resistance, representing a novel...
High-risk neuroblastoma remains a clinically challenging pediatric cancer, with an approximate five-year survival rate of ~60%. Frontline therapy for this group patients includes surgery and intensive chemotherapy that involves combinations the tubulin inhibitor vincristine several other chemotherapeutics. Unfortunately, unresponsiveness to relapse are common, tumors often displaying resistance vincristine. Recently, we characterized novel set inhibitors distinct from bind within colchicine...
Stress exposure or increased levels of corticotropin-releasing factor (CRF) induce hippocampal tau phosphorylation (tau-P) in rodent models, a process that is dependent on the type-1 CRF receptor (CRFR1). Although these preclinical studies stress-induced tau-P provide mechanistic insight for epidemiological work identifies stress as risk Alzheimer's disease (AD), actual impact neuronal function remains unclear. To determine functional consequences tau-P, we developed novel mouse cell culture...
Abstract Malignant rhabdoid tumor (MRT) is driven by the loss of SNF5 subunit SWI/SNF chromatin remodeling complex and then thought to be maintained residual (rSWI/SNF) complexes that remain present in absence SNF5. rSWI/SNF subunits colocalize extensively on with transcription factor MYC, an oncogene identified as a novel driver MRT. Currently, role modulating MYC activity has neither been delineated nor direct link between other oncogenes uncovered. Here, we expose connection oncogenic...