A5009311232- CAR-T cell therapy research
- Immune Cell Function and Interaction
- Cancer Immunotherapy and Biomarkers
- Immunotherapy and Immune Responses
- T-cell and B-cell Immunology
- Epigenetics and DNA Methylation
- Signaling Pathways in Disease
- Genetic Neurodegenerative Diseases
- Retinal Diseases and Treatments
- Mitochondrial Function and Pathology
- Histone Deacetylase Inhibitors Research
- Hereditary Neurological Disorders
- Endoplasmic Reticulum Stress and Disease
- CRISPR and Genetic Engineering
- Connexins and lens biology
- Retinopathy of Prematurity Studies
- Pancreatic function and diabetes
- Lipid Membrane Structure and Behavior
- Immune responses and vaccinations
- Diabetes and associated disorders
- Mesenchymal stem cell research
- Sphingolipid Metabolism and Signaling
- Diabetes Management and Research
- Muscle Physiology and Disorders
- RNA regulation and disease
St. Jude Children's Research Hospital
2020-2024
Children's Research Hospital
2020-2023
The University of Texas Southwestern Medical Center
2023
Stanford University
2023
University of Michigan
2023
Thomas Jefferson University Hospital
2023
University of Tennessee Health Science Center
2012-2021
RxBio (United States)
2018
DNMT3A deletion preserves CAR T cell functionality during prolonged stimulation.
Huntington's Disease (HD) is an autosomal dominant progressive neurodegenerative disorder characterized by cognitive, behavioral and motor dysfunctions. HD caused a CAG repeat expansion in exon 1 of the gene that translated into expanded polyglutamine tract encoded protein, huntingtin (HTT). While most significant neuropathology occurs striatum, other brain regions are also affected play important role pathology. To date there no cure for HD, recently strategies aiming at silencing HTT...
Epigenetic reinforcement of T cell exhaustion is known to be a major barrier limiting responses during immunotherapy. However, the core epigenetic regulators restricting antitumor immunity prolonged antigen exposure are not clear. We investigated three commonly mutated that promote clonal hematopoiesis determine whether they affect stemness and response checkpoint blockade CD8 cells lacking Dnmt3a, Tet2, or Asxl1 preserved progenitor-exhausted (Tpex) population for more than 1 year chronic...
Abstract Chronological aging correlates with epigenetic modifications at specific loci, calibrated to species lifespan. Such ‘epigenetic clocks’ appear conserved among mammals, but whether they are cell autonomous and restricted by maximal organismal lifespan remains unknown. We used a multilifetime murine model of repeat vaccination memory T transplantation test tracks cellular replication if such clocks continue ‘counting’ beyond Here we found that tick independently host age through four...
Early-stage diabetic retinopathy (DR) is characterized by neurovascular defects. In this study, we hypothesized that human adipose-derived stem cells (ASCs) positive for the pericyte marker CD140b, or their secreted paracrine factors, therapeutically rescue early-stage DR features in an Ins2Akita mouse model. mice at 24 weeks of age received intravitreal injections CD140b-positive ASCs (1000 cells/1 μL) 20× conditioned media from cytokine-primed (ASC-CM, 1 μL). Age-matched wildtype saline...
Hereditary sensory and autonomic neuropathies (HSANs) encompass a group of genetically inherited disorders characterized by dysfunctions. Familial dysautonomia (FD), also known as HSAN type III, is an autosomal recessive disorder that affects 1/3600 live births in the Ashkenazi Jewish population. The disease caused abnormal development progressive degeneration nervous systems inevitably fatal, with only 50% patients reaching age 40. FD mutation intron 20 Ikbkap gene results severe reduction...
Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease that affects the development and survival of sensory autonomic neurons. FD caused by mRNA splicing mutation in intron 20 IKBKAP gene results a tissue-specific skipping exon corresponding reduction inhibitor kappaB kinase complex-associated protein (IKAP), also known as Elongator complex 1. To date, several promising therapeutic candidates for have been identified target underlying defect, increase functional IKAP...
To gain insight into the signaling determinants of effector-associated DNA methylation programming among CD8 T cells, we explore role interleukin (IL)-12 in imprinting IFNg expression during cell priming. We observe that anti-CD3/CD28-mediated stimulation human naive cells is not sufficient to induce substantial demethylation promoter. However, anti-CD3/CD28 presence inflammatory cytokine, IL-12, results stable locus commensurate with expression. IL-12-associated coupled division through...
Abstract Diabetic retinopathy (DR) is the leading cause of vision loss among working‐age adults. The interplay between hyperglycemia and endothelial activation in inducing endoplasmic reticulum (ER) stress pathways visual deficits DR not fully understood. To address this, we used a mouse model chronic vascular using endothelial‐specific tumor necrosis factor‐α (TNF‐α)‐expressing (tie2‐TNF) mice to induce diabetes with streptozotocin. At 4 weeks post streptozotocin, significant 2‐fold 10‐fold...
The immune system undergoes a progressive functional remodeling with age. Understanding how age bias shapes antitumor immunity is essential in designing effective immunotherapies, especially for pediatric patients. Here, we explore CD8 + T cell responses generated young (prepubescent) and adult (presenescent) mice. Using an MHCI-deficient tumor model, observed that tumor-reactive cells expanded tumor-bearing (TB) mice acquired terminally differentiated phenotype characterized by...
Diarrheal disease is a severe global health problem. It estimated that secretory diarrhea causes 2.5 million deaths annually among children under the age of five in developing world. A critical barrier treating diarrheal lack easy-to-use effective treatments. While antibiotics may shorten length and severity diarrhea, oral rehydration remains primary approach managing diarrhea. Existing treatments mostly depend on reconstituting medicines with water often contaminated which can be an...
Mitochondria dysfunction occurs in the aging brain as well several neurodegenerative disorders and predisposes neuronal cells to enhanced sensitivity neurotoxins. 3-nitropropionic acid (3-NP) is a naturally occurring plant fungal neurotoxin that causes neurodegeneration predominantly striatum by irreversibly inhibiting tricarboxylic respiratory chain enzyme, succinate dehydrogenase (SDH), main constituent of mitochondria complex II. Significantly, although 3-NP-induced inhibition SDH all...
CD8 T cell memory differentiation endows cells with an ability to rapidly induce effector functions upon pathogen re-encounter. While it is well established that substantial epigenetic remodeling occurs during the stage of immune response, signaling events imprint these stable programs are not well-defined. To gain insight into determinants effector-associated programming among cells, we explored role IL-12 in imprinting IFNg expression human priming. We observed TCR-mediated stimulation...
Increased microvessel permeability is a major characteristic of lung inflammation. We showed inhibiting connexin 43 (Cx43)‐containing gap junctions blunts increases in microvessels due to an inflammatory insult. However, it unclear whether Cx43 levels directly influence the endothelial barrier. Toward this, we cultured rat microvascular cells (RLMVEC) on transwell inserts and determined via flux FITC dextran 40 kd (FDx40) across monolayer. In vehicle‐treated monolayers, FDx40 fluorescence...
Background: KRAS is the most commonly mutated oncogene in Lung adenocarcinoma (LUAD).Co-occurring mutations tumor suppressors and a master kinase LKB1/ STK11 or TP53 define major subgroups of KRASmutant LUAD with distinct biology therapeutic vulnerabilities.Inactivating LKB1 occur 31% mutant LUAD, resulting approximately 10,000-15,000 deaths annually US.KRAS comutated (KL) lung tumors represent one aggressive subtypes are resistant to immune checkpoint blockade (ICB) therapies.Thus, there...
Abstract As the immune system ages, protective capacity from established immunological memory wanes over time and is often referred to as senescence. Yet molecular hallmarks of lymphocyte age replicative senescence remain largely undefined. Here we report our use a multi-lifetime murine model repeat vaccination define core epigenetic signature coupled T cells that evade Through adoptive transfer boosting period approximately four mouse lifetimes, became enriched for repressive DNA...
Abstract Differentiation of CD8 T cells into a terminally exhausted state is major hurdle limiting efficacy both immune checkpoint blockade and adoptive cellular immunotherapy approaches. Prior studies describing disruption the epigenetic regulators DNMT3A TET2 in have revealed critical role DNA methylation repressing proliferative capacity effector potential during exhaustion. Disruption these genes has also been noted to preserve hematopoietic stem (HSCs), resulting clonal hematopoiesis...
<h3>Background</h3> The success of CAR T-cell immunotherapy depends on the differentiation status and metabolic fitness product. In current CART manufacturing protocols, activation leads to irreversible differentiation. Our recent work showed that nonactivated T-cells can be generated within 24 hours, eliminating need for or <i>ex vivo</i> expansion. We assert this process retains maximal Interleukin 18 (IL-18) is a proinflammatory cytokine regulates adoptively transferred T-cells, IL-18...
Abstract Recent advances in T cell-based immunotherapies have revolutionized treatment strategies for several types of cancers; however, approaches that rely on endogenous cell responses experienced limited success pediatric populations, a pattern primarily attributed to the relatively low mutational burden characteristic tumors. Here, we report our analysis CD8 cells isolated from diverse set solid tumors, documenting an enrichment with antigen-experienced phenotype (i.e., high PD1...
SUMMARY CD8 T cell memory differentiation endows cells with an ability to rapidly induce effector functions upon pathogen re-encounter. While it is well established that substantial epigenetic remodeling occurs during the stage of immune response, signaling events imprint these stable programs are not well-defined. To gain insight into determinants effector-associated programming among cells, we explored role IL-12 in imprinting IFNg expression human priming. We observed TCR-mediated...
Abstract Cancer immunotherapeutic approaches that rely on endogenous T cell responses have shown limited success in children, a pattern attributed to the low mutational burden of pediatric tumors. Here, we report CD8 cells isolated from diverse set solid tumors are enriched for an antigen-experienced phenotype. The ability immune checkpoint blockade therapy (ICBT) trigger anti-tumor despite presence activated cells, prompted us explore alternative underlying mechanisms restricting responses....