A5019618945- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- Genetic Neurodegenerative Diseases
- Alzheimer's disease research and treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Pluripotent Stem Cells Research
- S100 Proteins and Annexins
- Glutathione Transferases and Polymorphisms
- Cancer Mechanisms and Therapy
- Erythropoietin and Anemia Treatment
- Advanced Glycation End Products research
- CRISPR and Genetic Engineering
- Neuroscience of respiration and sleep
- Mitochondrial Function and Pathology
- RNA Interference and Gene Delivery
- Histone Deacetylase Inhibitors Research
- Respiratory and Cough-Related Research
- Lymphoma Diagnosis and Treatment
Stanford University
2023-2025
Pomona College
2021-2023
The University of Melbourne
2021
Kinases are critical regulators of cellular function that commonly implicated in the mechanisms underlying disease. Most drugs target kinases molecules inhibit their catalytic activity, but here we used chemically induced proximity to convert kinase inhibitors into activators therapeutic genes. We synthesized bivalent link ligands transcription factor B cell lymphoma 6 (BCL6) cyclin-dependent (CDKs). These relocalized CDK9 BCL6-bound DNA and directed phosphorylation RNA polymerase II. The...
Tumor necrosis factor-α (TNF-α) plays a central role in Alzheimer's disease (AD) pathology, making biologic TNF-α inhibitors (TNFIs), including etanercept, viable therapeutics for AD. The protective effects of TNFIs on AD hallmark pathology (Aβ deposition and tau pathology) have been demonstrated. However, the Aβ-independent not reported. Existing do cross blood-brain barrier (BBB), therefore we engineered BBB-penetrating TNFI by fusing extracellular domain type-II human receptor (TNFR) to...
Developing cancer therapies that induce robust death of the malignant cell is critical to prevent relapse. Highly effective strategies, such as immunotherapy, exemplify this observation. Here we provide structural and molecular underpinnings for an approach leverages chemical induced proximity produce specific killing diffuse large B lymphoma, most common non-Hodgkin's lymphoma. We develop KAT-TCIPs (lysine acetyltransferase transcriptional/epigenetic inducers proximity) redirect p300 CBP...
ABSTRACT Protein kinases are disease drivers whose therapeutic targeting traditionally centers on inhibition of enzymatic activity. Here chemically induced proximity is leveraged to convert kinase inhibitors into context-specific activators genes. Bivalent molecules that link ligands the transcription factor B-cell lymphoma 6 (BCL6) ATP-competitive cyclin-dependent (CDKs) were developed re-localize CDK BCL6-bound loci chromatin and direct phosphorylation RNA Pol II. The resulting BCL6-target...
Vagal sensory neurons contribute to the symptoms and pathogenesis of inflammatory pulmonary diseases through processes that involve changes their morphological functional characteristics. The alarmin high mobility group box-1 (HMGB1) is an early mediator inflammation can have actions on in a range settings. We hypothesized HMGB1 regulate growth function vagal we set out investigate this mechanisms involved. Culturing primary from wildtype mice presence significantly increased neurite...
ABSTRACT Genes that drive the proliferation, survival, invasion and metastasis of malignant cells have been identified for many human cancers 1–6 . Independent studies cell death pathways eliminate good organism 7–10 The coexistence with driver mutations suggest cancer could be rewired to activate death. We invented a new class molecules: TCIPs (Transcriptional/Epigenetic Chemical Inducers Proximity) recruit endogenous driver, or downstream transcription factor, promoters genes thereby...
Summary Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by striatal atrophy. Reduced trophic support due to decreased levels of neurotrophins (NTs), mainly brain-derived neurotrophic factor (BDNF), contributes importantly HD pathogenesis; restoring NTs has significant therapeutic potential. Human pluripotent stem cells (hPSC) offer a scalable platform for NT delivery but potential safety risks including teratoma formation. We engineered hPSCs...
Abstract Conventional pharmacotherapy in oncology centers on target-centric silencing of aberrant protein function through small molecule inhibitors, degraders, or CRISPR/RNAi. In contrast, here we leverage induced proximity to develop pharmacology that activates dominant signaling pathways for a therapeutic effect. To this concept, describe new class bivalent molecules reprogram cancer-driving gene expression activate cell death diffuse large B lymphomas (DLBCL). These molecules, called...
Erythropoietin (EPO), a hematopoietic neurotrophin, is potential therapeutic for Alzheimer's disease (AD) but has limited blood-brain barrier (BBB) permeability. EPO fused to chimeric transferrin receptor monoclonal antibody (cTfRMAb) enters the brain via TfR-mediated transcytosis across BBB. We previously showed that cTfRMAb-EPO protective in mouse model of amyloidosis, its effects on tauopathy are not known. Given amyloid and tau pathology characteristics AD, were studied (PS19)....