A5063920766- Extracellular vesicles in disease
- RNA Interference and Gene Delivery
- Monoclonal and Polyclonal Antibodies Research
- Immune cells in cancer
- Biosimilars and Bioanalytical Methods
- MicroRNA in disease regulation
- interferon and immune responses
- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
- Congenital heart defects research
- Receptor Mechanisms and Signaling
- Nanoplatforms for cancer theranostics
- Ubiquitin and proteasome pathways
- Prostate Cancer Treatment and Research
- Liver physiology and pathology
- Immunotherapy and Immune Responses
- Liver Disease Diagnosis and Treatment
- Genomic variations and chromosomal abnormalities
- Cannabis and Cannabinoid Research
- RNA Research and Splicing
- Developmental Biology and Gene Regulation
- Phosphodiesterase function and regulation
- Genetics and Neurodevelopmental Disorders
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- PI3K/AKT/mTOR signaling in cancer
Sanofi (France)
2019
Sanofi (Mexico)
2019
Inflammation Research Foundation
2019
AMAG Pharmaceuticals (United States)
2018
Sanofi (United States)
2008-2013
The University of Texas Southwestern Medical Center
2012
Advanced Pharma
2006-2009
Howard Hughes Medical Institute
2003
University of Utah
2003
Johnson University
2003
Extracellular vesicles (EVs) are an important intercellular communication system facilitating the transfer of macromolecules between cells. Delivery exogenous cargo tethered to EV surface or packaged inside lumen key strategies for generating therapeutic EVs. We identified two "scaffold" proteins, PTGFRN and BASP1, that preferentially sorted into EVs enable high-density display luminal loading a wide range molecules, including cytokines, antibody fragments, RNA binding vaccine antigens,...
Effectiveness of checkpoint immunotherapy in cancer can be undermined by immunosuppressive tumor-associated macrophages (TAMs) with an M2 phenotype. Reprogramming TAMs toward a proinflammatory M1 phenotype is novel approach to induce antitumor immunity. The controlled key transcription factors such as signal transducer and activator 6 (STAT6), which have been “undruggable” selectively TAMs. We describe engineered exosome therapeutic candidate delivering antisense oligonucleotide (ASO)...
Abstract Cyclic dinucleotide (CDN) agonists of the STimulator InterferoN Genes (STING) pathway have shown immune activation and tumor clearance in pre-clinical models. However, CDNs administered intratumorally also promote STING leading to direct cytotoxicity many cell types microenvironment (TME), systemic inflammation due rapid extravasation CDN, ablation TME. These result a failure establish immunological memory. ExoSTING, an engineered extracellular vesicle (EV) exogenously loaded with...
The promise of IL12 as a cancer treatment has yet to be fulfilled with multiple tested approaches being limited by unwanted systemic exposure and unpredictable pharmacology. To address these limitations, we generated exoIL12, novel, engineered exosome therapeutic that displays functional on the surface an exosome. exosomal expression was achieved via fusion abundant protein PTGFRN resulting in equivalent potency vitro recombinant (rIL12) demonstrated IFNγ production. Following intratumoral...
The murine prostate is a structure that made up of four distinct lobes; the dorsal and lateral prostates (often grouped together as dorsolateral prostate), anterior (coagulating gland) ventral prostate. Previous work has implicated Hox genes in development these structures, but how each lobe acquires unique identities for specific functions not been addressed. In this study, prostate-specific function Hoxb13 described. Mice lacking show normal numbers duct tips, mice mutant both Hoxd13...
The mechanisms by which homeoproteins bind selectively to target genes in vivo have long remained unresolved. Here we report that PIAS1 confers DNA-binding specificity on the Msx1 homeoprotein regulating its subnuclear localization and proximity genes. We demonstrate interaction of with PIAS1, but not sumoylation, is required for function as an inhibitor myoblast differentiation through repression myogenic regulatory genes, such MyoD . find enables a key element , CER, cells distinguish CER...
The cannabinoid receptor 1 (CB<sub>1</sub>R) is required for body weight homeostasis and normal gastrointestinal motility. However, the specific cell types expressing CB<sub>1</sub>R that regulate these physiological functions are unknown. widely expressed, including in neurons of parasympathetic branches autonomic nervous system. vagus nerve has been implicated regulation several aspects metabolism energy balance (e.g., food intake glucose balance), To directly test relevance on metabolic...
Prodrugs engineered for preferential activation in diseased versus normal tissues offer immense potential to improve the therapeutic indexes (TIs) of preclinical and clinical-stage active pharmaceutical ingredients that either cannot be developed otherwise or whose efficacy tolerability it is highly desirable improve. Such approaches, however, often suffer from trial-and-error design, precluding predictive synthesis optimization. Here, using bromodomain extra-terminal (BET) protein...
Cannabinoid receptor CB1 is expressed abundantly in the brain and presumably peripheral tissues responsible for energy metabolism. It unclear if antiobesity effects of rimonabant, a antagonist, are mediated through central or receptors. To address this question, we generated transgenic mice with nervous system (CNS)-specific knockdown (KD) CB1, by expressing an artificial microRNA (AMIR) under control neuronal Thy1.2 promoter. In mutant mice, expression was reduced spinal cord, whereas no...
Although the underlying neurobiology of major mental illness (MMI) remains unknown, emerging evidence implicates a role for oligodendrocyte-myelin abnormalities. Here, we took advantage large family carrying balanced t(1;11) translocation, which substantially increases risk MMI, to undertake both diffusion tensor imaging and cellular studies evaluate consequences translocation on white matter structural integrity biology. This disrupts among others DISC1 gene plays crucial in brain...
The neuromodulatory gene DISC1 is disrupted by a t(1;11) translocation that highly penetrant for schizophrenia and affective disorders, but how this affects function incompletely understood. N-methyl-D-aspartate receptors (NMDAR) play central role in synaptic plasticity cognition, are implicated the pathophysiology of through genetic functional studies. We show NMDAR subunit GluN2B complexes with DISC1-associated trafficking factor TRAK1, while interacts GluN1 regulates dendritic motility...
Eicosanoids are lipid-mediator molecules with key roles in inflammatory skin diseases, such as psoriasis. released close to the source of inflammation, where they elicit local pleiotropic effects and dysregulations. Monitoring mediators directly lesions could provide new insights therapeutic possibilities. Here, we analyzed dermal interstitial fluid samples obtained by open-flow microperfusion a rat model inflammation. We developed solid-phase extraction ultra-HPLC/MS/MS method reliably...
Numerous assays have been developed to investigate the interactions between G-protein–coupled receptors (GPCRs) and their ligands since GPCRs are key therapeutic targets. Reporter-based using cAMP response element (CRE) coupled with bioluminescence from a luciferase reporter used extensively in vitro high-throughput screens (HTS) of large chemical compound libraries. We generated transgenic mouse model (CRE luc) under control synthetic promoter that contains several CREs, which supports...
Abstract Background: The Stimulator of Interferon Genes (STING) pathway is an attractive target in immuno-oncology. Selective activation the STING antigen presenting cells (APCs) essential for eliciting a potent and specific anti-tumor immune response. ubiquitously expressed normal including T endothelial cells. Direct intra-tumoral administration free agonist results all cells, resulting loss viability tissue damage, systemic due to vascular leakage. Exosomes are efficient natural messenger...
Abstract Tumor-associated macrophages (TAMs) are potent drivers of an immunosuppressive tumor microenvironment and may be attractive therapeutic target. Experimental therapies tested thus far block myeloid cell differentiation, leading to ineffective antigen presentation minimal antitumor activity. Exosomes serve as efficient, natural, intercellular communication system that can deliver nucleic acids other macromolecules. We have developed novel, engineered exosome candidates selectively...
Abstract Background: Tumor-associated macrophages (TAMs) promote tumor progression and resistance to immune checkpoint inhibitors are thus attractive targets for cancer immunotherapy. The STAT6 transcriptional network is an important driver of the immune-suppressive M2 macrophage program in microenvironment (TME). Previous attempts therapeutically target these networks have not been successful. Exosomes serve as efficient, natural, intercellular communication system that can deliver nucleic...
Background: The Stimulator of Interferon Genes (STING) pathway is an attractive target in immuno-oncology. Selective activation the STING antigen presenting cells (APCs) essential for eliciting a potent and specific anti-tumor immune response. ubiquitously expressed normal including T endothelial cells. Direct intra-tumoral administration free agonist results all cells, resulting loss viability tissue damage, systemic due to vascular leakage. Exosomes are efficient natural messenger system...
<h3>Background</h3> The promise of Interleukin-12 as a cancer treatment has yet to be fulfilled with multiple tested approaches being limited by unwanted systemic exposure and unpredictable pharmacology. To address these limitations, we generated exoIL-12™, novel, engineered-exosome therapeutic that displays functional IL-12 on the surface an exosome. <h3>Methods</h3> exosomal expression was achieved via fusion abundant protein PTGFRN. Potency assessed in vitro using human PBMCs or murine...