Project description:FAAH expresson is induced in Sle2 splenic B cells. Increased peripheral B cell receptor revision, or selective peripheral expansion of BCR-revised B-cells, may lead to systemic autoimmunity, and FAAH is a lupus susceptibility gene that could regulate this process in Sle2 mice.
Project description:FAAH expresson is induced in Sle2 splenic B cells. Increased peripheral B cell receptor revision, or selective peripheral expansion of BCR-revised B-cells, may lead to systemic autoimmunity, and FAAH is a lupus susceptibility gene that could regulate this process in Sle2 mice. To determine the gene expression profile in peripheral B cells from Sle2 mice (compared to B6 mice), we isolated splenic B cells from these two strains of mice, extracted the total mRNA and performed the microarray analysis Please note that Sle2 mouse is a congenic strain that harbors the Sle2 locus from Chromosome 4 of NZM2410 strain in a B6 background and Sle2 is the name of the lupus susceptibility locus.
Project description:Benson2014 - FAAH inhibitors for the treatment of osteoarthritic pain
Evaluation of fatty acid amide hydrolase (FAAH) as a target for osteoarthritic pain in humans, using an integrated systems pharmacology model.
The SBML version of the model is obtained from the supplementary material of the corresponding paper (see below).
This model is described in the article:
A systems pharmacology perspective on the clinical development of Fatty Acid amide hydrolase inhibitors for pain.
Benson N, Metelkin E, Demin O, Li GL, Nichols D, van der Graaf PH.
CPT Pharmacometrics Syst Pharmacol. 2014 Jan 15;3:e91.
Abstract:
The level of the endocannabinoid anandamide is controlled by fatty acid amide hydrolase (FAAH). In 2011, PF-04457845, an irreversible inhibitor of FAAH, was progressed to phase II clinical trials for osteoarthritic pain. This article discusses a prospective, integrated systems pharmacology model evaluation of FAAH as a target for pain in humans, using physiologically based pharmacokinetic and systems biology approaches. The model integrated physiological compartments; endocannabinoid production, degradation, and disposition data; PF-04457845 pharmacokinetics and pharmacodynamics, and cannabinoid receptor CB1-binding kinetics. The modeling identified clear gaps in our understanding and highlighted key risks going forward, in particular relating to whether methods are in place to demonstrate target engagement and pharmacological effect. The value of this modeling exercise will be discussed in detail and in the context of the clinical phase II data, together with recommendations to enable optimal future evaluation of FAAH inhibitors.
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Project description:The small heterodimer partner (SHP) regulates fatty acid oxidation and lipogenesis in the liver by regulating peroxisome proliferator-activated receptor (PPAR) γ expression. SHP is also abundantly expressed in the myocardium. Therefore, we investigated the myocardial gene expression in a SHP deletion animal model.
Project description:Wnt signaling is critical for normal skeletal development as well as whole-body metabolic function. In this study, we described a previously unrecognized function for Wnt-Lrp5 signaling in the osteoblast that allows bone to acquire the resources necessary to fuel bone formation. Mice lacking the Lrp5 co-receptor specifically in osteoblasts and osteocytes exhibit the expected reductions in postnatal bone mass and also develop peripheral adiposity with corresponding reductions in energy expenditure. Conversely, mice expressing a high-bone mass mutant Lrp5 allele are leaner with reduced plasma triglyceride and free fatty acid levels. In this context, Wnt-initiated signals downstream of Lrp5, but not Lrp6, regulate the expression of key enzymes required for fatty acid β-oxidation. These results suggest that Wnt-Lrp5 signaling regulates basic cellular activities beyond those associated with fate-specification and differentiation in bone and that the skeleton influences global energy homeostasis via mechanisms independent of osteocalcin and glucose metabolism Total RNA isolated from cultures of Lrp5-deficient osteoblasts differentiated for 7 days in vitro compared to control osteoblasts
Project description:The mission of B lymphocytes is considered to reside primarily in immunoglobulin production; however, the success of B cell depletion in autoimmune diseases previously thought to be T cell-mediated suggests that some B cells fulfill other roles in autoimmunity. We examined the recently identified human B1 cell population for T cell stimulatory activity. We found two kinds of B1 cells that are distinguished by multiple surface markers and distinct transcriptomic profiles. In both umbilical cord and adult peripheral blood, the larger of the two, which is CD11b-, constitutes about 90% of B1 cells, whereas the smaller of the two, which is CD11b+, constitutes about 10% of B1 cells. These B1 cell populations differ functionally. CD11b- B1 cells spontaneously secrete much more IgM than CD11b+ B1 cells. In contrast, CD11b+ B1 cells express more CD86, and efficiently stimulate more T cell expansion, than CD11b- B1 cells. These CD11b+ B1 cells are markedly elevated in lupus patients and express increased CD86 and increased T cell stimulating activity in disease. This work distinguishes a novel, T cell-interacting B1 cell population whose expression and activity may be a reflection of, and a therapeutic target in, autoimmune disease. abstract Four groups each group comprising 3 samples for a total of 12 samples of human B cells were analyzed
Project description:The goal of this study was to determine what genes are up- and down-regulated in response to lupus immune complexes in total peripheral blood mononuclear cells (PBMCs). Our results have shown that novel genes are induced by immune complexes that are likely important for lupus pathogenesis plus that C1q regulates these pathways and induces multiple new pathways not previously identified. Total RNA was isolated from PBMCs from 2 donors after 5 hours with the following condiitons: 1) Unstimulated, 2) Lupus immune complex alone, 3) Lupus immune complex + C1q, 4) C1q alone