Project description:The adenosine 2A receptor (A2AR) is expressed on regulatory T cells (Tregs), but the functional significance is currently unknown. We compared the gene expression between wild-type (WT) and A2AR knockout (KO) Tregs and between WT Tregs treated with vehicle or a selective A2AR agonist. FACS-sorted GFP positive Tregs from WT or A2AR KO FoxP3GFP mouse spleen and lymph nodes were incubated 18 hr with vehicle (DMSO), a separate set of WT Tregs were incubated with the selective A2AR agonist ATL1222 10 nM (Dogwood Pharmaceuticals, Inc.) for 18 hr prior to RNA isolation.
Project description:The adenosine 2A receptor (A2AR) is expressed on regulatory T cells (Tregs), but the functional significance is currently unknown. We compared the gene expression between wild-type (WT) and A2AR knockout (KO) Tregs and between WT Tregs treated with vehicle or a selective A2AR agonist.
Project description:Analysis of venticular myocardium from adenosine 2A receptors (A2AR) knockouts following LPS stimulation. Results provide insight into the molecular components of A2AR mediated protection, but also reveal pathogenetic components of endotoxemic myocarditis as a result of LPS exposure. These findings demonstrate that intrinsic A2AR activity exerts limited transcriptional effects in unstressed heart, modifying G-coupled cAMP/PKA signal paths. LPS-dependent injury and dysfunction is associated with profound up-regulation of inflammatory/immune processes, fibrotic and cell death paths, and NF-kB, Erk/MAPK and JAK/Stat signaling, with shifts in multiple determinants of cardiac contraction and survival. Intrinsic A2AR activity modulates key aspects of these inflammatory responses, involving MAPK, JAK/Stat and NF-kB signaling Total RNA obtained from adenosine 2A receptor knockout or wild-type murine ventricular myocardium that were treated for 24 hours with either saline or lipopolysaccharide (n=4/group).
Project description:Analysis of venticular myocardium from adenosine 2A receptors (A2AR) knockouts following LPS stimulation. Results provide insight into the molecular components of A2AR mediated protection, but also reveal pathogenetic components of endotoxemic myocarditis as a result of LPS exposure. These findings demonstrate that intrinsic A2AR activity exerts limited transcriptional effects in unstressed heart, modifying G-coupled cAMP/PKA signal paths. LPS-dependent injury and dysfunction is associated with profound up-regulation of inflammatory/immune processes, fibrotic and cell death paths, and NF-kB, Erk/MAPK and JAK/Stat signaling, with shifts in multiple determinants of cardiac contraction and survival. Intrinsic A2AR activity modulates key aspects of these inflammatory responses, involving MAPK, JAK/Stat and NF-kB signaling
Project description:To understand the mechanisms through which JunB regulates Tregs-mediated immune regulation, we examined the global gene expression profiles in the JunB WT and KO Tregs by performing RNA sequencing (RNA-seq) analysis.
Project description:Introgressed variants from other species can be an important source of genetic variation because they may arise rapidly, can include multiple mutations on a single haplotype, and have often been pretested by selection in the species of origin. Although introgressed alleles are generally deleterious, several studies have reported introgression as the source of adaptive alleles-including the rodenticide-resistant variant of Vkorc1 that introgressed from Mus spretus into European populations of Mus musculus domesticus. Here, we conducted bidirectional genome scans to characterize introgressed regions into one wild population of M. spretus from Spain and three wild populations of M. m. domesticus from France, Germany, and Iran. Despite the fact that these species show considerable intrinsic postzygotic reproductive isolation, introgression was observed in all individuals, including in the M. musculus reference genome (GRCm38). Mus spretus individuals had a greater proportion of introgression compared with M. m. domesticus, and within M. m. domesticus, the proportion of introgression decreased with geographic distance from the area of sympatry. Introgression was observed on all autosomes for both species, but not on the X-chromosome in M. m. domesticus, consistent with known X-linked hybrid sterility and inviability genes that have been mapped to the M. spretus X-chromosome. Tract lengths were generally short with a few outliers of up to 2.7 Mb. Interestingly, the longest introgressed tracts were in olfactory receptor regions, and introgressed tracts were significantly enriched for olfactory receptor genes in both species, suggesting that introgression may be a source of functional novelty even between species with high barriers to gene flow.
Project description:Translational research is commonly performed in the C57B6/J mouse strain, chosen for its genetic homogeneity and phenotypic uniformity. Here, we evaluate the suitability of the white-footed deer mouse (Peromyscus leucopus) as a model organism for aging research, offering a comparative analysis against C57B6/J and diversity outbred (DO) Mus musculus strains. Our study includes comparisons of body composition, skeletal muscle function, and cardiovascular parameters, shedding light on potential applications and limitations of P. leucopus in aging studies. Notably, P. leucopus exhibits distinct body composition characteristics, emphasizing reduced muscle force exertion and a unique metabolism, particularly in fat mass. Cardiovascular assessments showed changes in arterial stiffness, challenging conventional assumptions and highlighting the need for a nuanced interpretation of aging-related phenotypes. Our study also highlights inherent challenges associated with maintaining and phenotyping P. leucopus cohorts. Behavioral considerations, including anxiety-induced responses during handling and phenotyping assessment, pose obstacles in acquiring meaningful data. Moreover, the unique anatomy of P. leucopus necessitates careful adaptation of protocols designed for Mus musculus. While showcasing potential benefits, further extensive analyses across broader age ranges and larger cohorts are necessary to establish the reliability of P. leucopus as a robust and translatable model for aging studies.
Project description:Colorectal cancers are the third most common type of cancer in the world. Peritoneal carcinomatosis and intraabdominal acid development occur in advanced stages of colorectal cancers.
It is known that the immune system plays an important role in tumor development or tumor eradication. Differentiation of T cells towards Th2 and regulatory T cells is also reported to be effective in tumor progression.
Among the mechanisms of escape from the immune system, changes in the tumor microenvironment play an important role. The role of regulatory T lymphocytes, a subgroup of T cells that play a regulatory role by suppressing the function of other T lymphocytes, is to reduce the chronic immune response against viruses, tumors and patients’s own antigens. The common feature of all Tregs is that they secrete one or more anti-inflammatory molecules such as IL-10, TGFβ or IL-35. High levels of Tregs have been found in peripheral blood, tumor tissue and lymph nodes in patients with malignancy.
In our study, it is aimed to evaluate whether there is a difference in intraabdominal ascites fluid T helper cytokine levels in patients with end-stage colorectal cancers compared to patients without malignancy.
Project description:T cell exhaustion is a state of functional decline in T cells, driven by chronic antigen exposure and inhibitory signals within the tumor microenvironment. Exhausted CD8+ T cells (Tex) derive from precursor exhausted T cells (Tpex), a self-renewing population responsible for the proliferative burst observed in anti-PD-1 therapies. Exhausted cells are exposed to adenosine in the tumor, yet the role of the CD73/adenosine axis and Tpex/Tex differentiation remains unclear. Using an in vitro model for CD8+ T cell exhaustion, we found that CD73 expression increased during Tpex formation and that its expression is negatively correlated with Tex generation. CD73-deficient (CD73KO) CD8⁺ T cells showed impaired activation and reduced progression to Tex. Moreover, we demonstrated that CD73 promotes transcriptional expression of the adenosine receptor A2A (A2AR) and the differentiation into IFNγ/TNFα-producing Tex cells. RNAseq analysis of exhausted CD73KO CD8+ T cells showed a more stem-like transcriptomic profile and enrichment in genes associated with the immune response than their WT counterpart. In vivo, co-transfer of naïve CD73 KO and WT tumor antigen-specific CD8⁺ T cells into tumor-bearing mice showed increased Tpex frequency and numbers among CD73KO cells in tumors. Conversely, in vitro exhaustion in the presence of A2AR agonists decreased Tex frequency and activation/exhaustion markers, while increasing CD73 and CD62L, markers associated with stemness. Supporting this, A2AR blockade with SYN115 in tumor-bearing mice reduced Tpex markers and increased Tex differentiation. Altogether, our data suggest CD73 promotes Tpex-to-Tex differentiation, whereas adenosine-A2AR signaling supports Tpex maintenance in the tumor microenvironment.