A5042027437- CAR-T cell therapy research
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Immune Response and Inflammation
- Immunotherapy and Immune Responses
- Immune cells in cancer
- CRISPR and Genetic Engineering
- RNA modifications and cancer
- Neuroinflammation and Neurodegeneration Mechanisms
- Cancer Immunotherapy and Biomarkers
- Diabetes and associated disorders
- Cell Adhesion Molecules Research
- Cancer-related molecular mechanisms research
- Advanced biosensing and bioanalysis techniques
- Protease and Inhibitor Mechanisms
- Atherosclerosis and Cardiovascular Diseases
- Innovation and Socioeconomic Development
- RNA Interference and Gene Delivery
- Virus-based gene therapy research
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Adipokines, Inflammation, and Metabolic Diseases
- Nanowire Synthesis and Applications
- Environmental Science and Water Management
- Advancements in Semiconductor Devices and Circuit Design
- Nanoparticle-Based Drug Delivery
National Institute of Allergy and Infectious Diseases
2019-2024
National Institutes of Health
2019-2023
Cancer Research Center
2009
Johns Hopkins University
2009
Hyland Software (United States)
1984
Adoptive cell therapy using engineered T receptors (TCRs) is a promising approach for targeting cancer antigens, but tumor-reactive TCRs are often weakly responsive to their target ligands, peptide-major histocompatibility complexes (pMHCs). Affinity-matured can enhance the efficacy of TCR-T also cross-react with off-target resulting in organ immunopathology. We developed an alternative strategy isolate TCR mutants that exhibited high activation signals coupled low-affinity pMHC binding...
Full T cell activation requires TCR engagement (signal 1) in the context of costimulation 2). Costimulation is required for maximal expression effector cytokines and prevention anergy. It has become increasingly clear that another major function to up-regulate metabolic machinery necessary function. In this report we demonstrate anergic cells are metabolically anergic, upon full stimulation (signals 1 plus 2) they fail support increased metabolism. These findings suggest one mechanism...
Significance It has been proposed that the spatial arrangement of ligands plays a key role in regulating downstream intracellular signals. Because methodological limitations precise ligand patterning, however, relationship between configuration clusters and signaling dynamics remains poorly understood. By developing DNA-based molecular “pegboard” for we demonstrated nanometer significant roles modulating signal transduction T cells. Ligand clustering not only affects triggering sensitivity...
Despite existing evidence for tuning of innate immunity to different classes bacteria, the molecular mechanisms used by macrophages tailor inflammatory responses specific pathogens remain incompletely defined. By stimulating mouse with a titration matrix TLR ligand pairs, we identified distinct stimulus requirements activating and inhibitory events that evoked diverse cytokine production dynamics. These regulatory were linked patterns distinguished between Gram-positive Gram-negative both in...
Checkpoint blockade revolutionized cancer therapy, but we still lack a quantitative, mechanistic understanding of how inhibitory receptors affect diverse signaling pathways. To address this issue, developed and applied fluorescent intracellular live multiplex signal transduction activity reporter (FILMSTAR) system to analyze PD-1-induced suppressive effects. These studies identified pathways triggered solely by TCR or requiring both CD28 inputs. Using presenting cells differing in PD-L1 CD80...
Apoptosis is a genetically regulated program of cell death that plays key role in immune disease processes. We identified EBF4, little-studied member the early B factor (EBF) family transcription factors, whole-genome CRISPR screen for regulators Fas/APO-1/CD95-mediated T death. Loss EBF4 increases half-life c-FLIP protein, and its presence Fas signaling complex impairs caspase-8 cleavage apoptosis. Transcriptome analysis revealed regulates molecules such as TBX21, EOMES, granzyme, perforin...
T cell receptor (TCR) engagement causes a global cellular response that entrains signaling pathways, cycle regulation, and death. The molecular regulation of mRNA translation in these processes is poorly understood. Using whole-genome CRISPR screen for regulators CD95 (FAS/APO-1)-mediated death, we identified AMBRA1, protein previously studied its roles autophagy, E3 ubiquitin ligase activity, cyclin regulation. cells lacking AMBRA1 resisted FAS-mediated death by down-regulating FAS...
Clustered regularly interspaced short palindromic repeats (CRISPR)-based methods have revolutionized genome engineering and the study of gene-phenotype relationships. However, modifying cells innate immune system, especially macrophages, has been challenging because cell pathology low targeting efficiency resulting from nucleic acid activation intracellular sensors. Likewise, lymphocytes adaptive system are difficult to modify using CRISPR-enhanced homology-directed repair inefficient or...
SUMMARY T cell receptor clustering plays a key role in triggering activation, but the relationship between spatial configuration of clusters and elicitation downstream intracellular signals remains poorly understood. We developed DNA-origami-based system that is easily adaptable to other cellular systems enables rich interrogation responses variety spatially defined inputs. Using chimeric antigen (CAR) model with relevance cancer therapy, we studied signaling dynamics at single resolution....
Abstract CRISPR (clustered regularly interspaced short palindromic repeats)-based methods have revolutionized genome engineering and the study of gene-phenotype relationships. However, modifying cells innate immune system, especially macrophages, has been challenging because cell pathology low targeting efficiency resulting from nucleic acid activation sensitive intracellular sensors. Likewise, lymphocytes adaptive system are largely refractory to CRISPR-enhanced homology-directed repair...