Project description:Progressive retinal atrophy (PRA) is a common cause of blindness in many pure and mixed breed dogs (Canis lupus familiaris). The typical onset of PRA begins with gradual night vision loss followed by day vision loss due to the death of rod and cone receptors, respectively. There are currently no mutations or genes reported to be causative or associated with PRA in the Hungarian Puli. In this study, we use an extensive list of 53 known PRA genes to screen for putative causal variants in this breed of dog.
Project description:Progesterone receptor (PR) is expressed from a single gene as two isoforms, PRA and PRB. In normal breast human tissue, PRA and PRB are expressed in equimolar ratios, but isoform ratio is altered during malignant progression, usually leading to high PRA:PRB ratios. We took advantage of a transgenic mouse model where PRA isoform is predominant (PRA transgenics) and identified the key transcriptional events and associated pathways underlying the preneoplastic phenotype in mammary glands of PRA transgenics as compared with normal wild-type littermates.
Project description:Progesterone receptor (PR) isoforms, PRA and PRB, both progesterone-independent and dependent modulated the biology of breast cancer cells. The different phenotypes in breast cancer mediated by PRA and PRB could due to the differences of their structures, leading to the distinct protein interacting partners and downstream signaling events of each receptor. Here, we constructed Tet-inducible HA-tagged PRA or HA-tagged PRB in T47DC42 breast cancer cells. We performed affinity purification coupled with SILAC mass spectrometry technique to comprehensively study PRA and PRB interacting partners in both liganded and unliganded conditions. To validate our findings, we applied both forward and reverse SILAC to effectively minimize experimental errors. These datasets will be useful in investigating PRA- and PRB-specific molecular mechanisms and can potentially be used as a database for subsequent experiments to identify novel PRA and PRB interacting proteins that differentially mediated different biological functions in breast cancer cells.
Project description:Background: C. elegans fed with a chemical inhibitor of glucose, namely 2-deoxy-D-glucose (DOG), exhibit considerably extended life span. DOG, in contradiction to D-glucose, cannot be metabolized in the glycolytic pathway. This results in the fact that less glucose is available for ATP production, and thus makes DOG-feeding of the roundworms equivalent to glucose restriction. The RNA-seq data comprises 4 age groups (1, 5, 10 and 20 days after L4) 11 samples: mRNA profiles of 1-day, 5-day and 10-day old worms as triplicates for DOG treatment; mRNA profiles of 20-day old worms as duplicates for DOG treatment
Project description:Examine the possible pro-inflammatory gene effects of alloantibody and complement on endothelial cells Microarray 3 Experiment performed three times on three separate microarrays using three separate HUVEC and PRA donors. In each experiment, there are four groups of HUVEC with three replicates per group treated for 4 hours in gelatin veronal buffer containing either complement-inactivated PRA serum, vehicle (gelatin veronal buffer), PRA serum, or non-PRA serum
Project description:Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Additionally, the two PR isoforms PRA and PRB, bind distinct genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and importantly, PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. This better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher anti-tumor activity of combination therapies of tamoxifen with PR antagonists and modulators. The study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist) from unique isoform and ligand-specific effects will guide the development of biomarkers for patient selection and translation of PR-targeted therapies to the clinic.
Project description:Prerenal azotemia (PRA) is a major cause of acute kidney injury (AKI) and uncommonly studied in preclinical models. Using a reverse translational approach, we developed a novel model of PRA that meets the clinical definition. 6 hours after furosemide administration to induce volume loss in wild type (WT) mice, measured GFR was 25% of baseline and returned to baseline after saline resuscitation at 48 hours. At 6 hours of PRA, plasma IL-6 was significantly increased, renal and liver histology were normal, renal and liver lactate were normal, and renal KIM-1 immunofluorescence was negative; 327 differentially regulated genes were upregulated in the liver and the acute phase response was the most significantly upregulated pathway; 25% of upregulated genes were reduced in IL-6-/-, and the acute phase response was the most significantly downregulated pathway. Three significantly upregulated genes were further investigated: NGAL, CXCL1, and haptoglobin; hepatic gene expression and plasma protein levels were all increased in WT PRA and were all reduced in IL-6-/- PRA. This work demonstrates previously unknown systemic effects of prerenal azotemia that includes systemic inflammation and IL-6 mediated upregulation of the hepatic acute phase response; we anticipate that these effects will have significant clinical consequences.
Project description:In this study, we dissect in detail the glial and immune responses associated to early stages of CAA. To do so, RNAseq gene expression analysis were performed in a mouse model for Familial Danish Dementia (FDD), a neurodegenerative disease characterized by the accumulation of Danish amyloid (ADan) in the vasculature. Findings observed in this CAA mouse model were complemented with primary culture assays.