Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TGF-beta is considered a negative regulator of hemopoietic stem and progenitor cells. We have previously shown that one TGF-beta isoform, TGF-beta2, is, in fact, a positive regulator of murine hemopoietic stem cell function in vivo. In vitro, TGF-beta2, but not TGF-beta1 and TGF-beta3, had a biphasic dose response on the proliferation of purified lin-Sca1(++)kit(+) (LSK) cells, with a stimulatory effect at low concentrations, which was subject to mouse strain-dependent variation. In this study we report that the stimulatory effect of TGF-beta2 on the proliferation of LSK cells increases with age and after replicative stress in C57BL/6, but not in DBA/2, mice. The age-related changes in the TGF-beta2 effect correlated with life span in BXD recombinant strains. The stimulatory effect of TGF-beta2 on the proliferation of LSK cells requires one or more nonprotein, low m.w. factors present in fetal calf and mouse sera. The activity of this factor(s) in mouse serum increases with age. Taken together, our data suggest a role for TGF-beta2 and as yet unknown serum factors in the aging of the hemopoietic stem cell compartment and possibly in organismal aging.
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PMID:The positive regulatory effect of TGF-beta2 on primitive murine hemopoietic stem and progenitor cells is dependent on age, genetic background, and serum factors. 1529 63

Adult somatic stem cells possess extensive self-renewal capacity, as their primary role is to replenish aged and functionally impaired tissues. We have previously shown that the stem cell pool in short-lived DBA/2 (D2) mice is reduced during aging, in contrast to long-lived C57BL/6 (B6) mice. This suggests the existence of a genetically determined mitotic clock operating in stem cells, which possibly limits organismal aging. In the study reported here, unfractionated bone marrow (BM) cells or highly purified Lin(-)Sca-1(+)c-kit(+) (LSK) cells were serially transplanted in lethally irradiated D2 and B6 mice. In both strains, serial transplantation resulted in a substantial loss of stem cell activity. However, as we estimate that in B6 mice, the maximum number of population doublings of primitive cells is approximately 30, in D2 mice this is only approximately 20, resulting in a 1,000-fold difference in expansion potential, irrespective of whether whole bone marrow or purified hematopoietic stem cells (HSCs) were transplanted. Interestingly, recipients reconstituted with serially transplanted BM cells were able to accept a freshly isolated graft without any further conditioning. Finally, we show that whereas transplantation of BM cells into healthy, nonconditioned, young B6 recipients does not lead to engraftment, young BM cells do engraft and provide multilineage reconstitution in nonirradiated aged mice. Our data clearly establish the relevance of an intrinsic, genetically controlled program associated with impaired stem cell functioning during aging.
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PMID:Impaired hematopoietic stem cell functioning after serial transplantation and during normal aging. 1562 25

The possible role of PGs and NO in the development of S&W of DBA/2J mice was investigated by evaluating the effects of dexamethasone, indometacin, mifepristone plus dexamethasone on the S&W, as well as of L-NAME both on the S&W in the electrocorticogram of DBA/2J mice and on morphine- and deltorphin II-induced EEG seizure in rabbits. The results of our data indicate that: a) Both dexamethasone and indometacin (1,10,100 microg/kg/i.p.) reduced the S&W of DBA/2J mice and mifepristone, a glucocorticoid receptor antagonist (1,10,100 microg/kg/i.p.), totally blocked the steroid effect. b) L-NAME (3-300 microg/mouse/ i.c.v.) dose-dependently reduced the S&W of DBA/2J mice whereas D-NAME at the same doses did not affect S&W of mice. The inhibitory effect of L-NAME on S&W of mice was dose-dependently reversed by L-arginine (L-ARG, 3-300 microg/mouse/ i.c.v.) but not by D-arginine. Finally, GTN its own (3-300 microg/mouse/ i.c.v.) significantly increased the S&W of mice and it was also able to reverse the inhibition on S&W of mice operated by L-NAME. c) Morphine and deltorphin II (100 microg/icv/toto) produce EEG seizure activity in rabbits and L-NAME (300 microg/i.c.v./toto), injected 15 min before morphine or deltorphin II, dose dependently prevented the EEG ictal episodes, the spiking activity and the synchronized EEG pattern induced by morphine or deltorphin II. The inhibitory effect of L-NAME on morphine or deltorphin II seizures was dose-dependently reversed by L-arginine (300 microg/icv/toto) but not by D-arginine. Finally, GTN on its own (300 microg/icv/toto) significantly increased morphine or deltorphin II seizures in the rabbit and it was also able to reverse the inhibition on morphine or deltorphin II seizures operated by L-NAME. These results provide a strong evidence that both PGs and NO may play a significant role in the development of brain excitability.
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PMID:The involvement of prostaglandins and nitric oxide in the development of brain excitability: a relationship study. 1885 75

Hematopoietic stem/progenitor cell (HSPC) traits differ between genetically distinct mouse strains. For example, DBA/2 mice have a higher HSPC frequency compared with C57BL/6 mice. We performed a genetic screen for micro-RNAs that are differentially expressed between LSK, LS(-)K(+), erythroid and myeloid cells isolated from C57BL/6 and DBA/2 mice. This analysis identified 131 micro-RNAs that were differentially expressed between cell types and 15 that were differentially expressed between mouse strains. Of special interest was an evolutionary conserved miR cluster located on chromosome 17 consisting of miR-99b, let-7e, and miR-125a. All cluster members were most highly expressed in LSKs and down-regulated upon differentiation. In addition, these microRNAs were higher expressed in DBA/2 cells compared with C57BL/6 cells, and thus correlated with HSPC frequency. To functionally characterize these microRNAs, we overexpressed the entire miR-cluster 99b/let-7e/125a and miR-125a alone in BM cells from C57BL/6 mice. Overexpression of the miR-cluster or miR-125a dramatically increased day-35 CAFC activity and caused severe hematopoietic phenotypes upon transplantation. We showed that a single member of the miR-cluster, namely miR-125a, is responsible for the majority of the observed miR-cluster overexpression effects. Finally, we performed genome-wide gene expression arrays and identified candidate target genes through which miR-125a may modulate HSPC fate.
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PMID:Genetic screen identifies microRNA cluster 99b/let-7e/125a as a regulator of primitive hematopoietic cells. 2212 44

Bruton's tyrosine kinase (Btk) is expressed in a variety of immune cells and previous work has demonstrated that blocking Btk is a promising strategy for treating autoimmune diseases. Herein, we utilized a tool Btk inhibitor, M7583, to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. In BXSB-Yaa lupus mice, Btk inhibition reduced autoantibodies, nephritis, and mortality. In the pristane-induced DBA/1 lupus model, Btk inhibition suppressed arthritis, but autoantibodies and the IFN gene signature were not significantly affected; suggesting efficacy was mediated through inhibition of Fc receptors. In vitro studies using primary human macrophages revealed that Btk inhibition can block activation by immune complexes and TLR7 which contributes to tissue damage in SLE. Overall, our results provide translational insight into how Btk inhibition may provide benefit to a variety of SLE patients by affecting both BCR and FcR signaling.
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PMID:Btk inhibition treats TLR7/IFN driven murine lupus. 2682 4

To investigate whether dysregulated selection of autoreactive marginal zone (MZ) B cells is involved in autoimmune diseases, we examined MZ B cell profile in multiple strains of mice, and found that type II collagen (CII)-reactive autoreactive CD80high MZ B cells spontaneously developed in the DBA/1, but not in C57BL/6 mice. CD80high MZ B cells that were characteristically found in DBA/1 mice expressed higher levels of TACI, SLAM3, and SLAM6 than the usual CD80low MZ B cells. Notably, the CD80high MZ B cells were more sensitive to ibrutinib, a Bruton's tyrosine kinase inhibitor, than CD80low MZ or follicular B cells and their transient depletion via intravenous injection of ibrutinib significantly delayed the induction of collagen-induced arthritis (CIA). In summary, we suggest that the positive selection of CII-reactive CD80high MZ B cells is a critical homeostatic process predisposing the DBA/1 mice to the CIA induction.
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PMID:Positive selection of type II collagen-reactive CD80high marginal zone B cells in DBA/1 mice. 2816 95

Glaucoma is a leading cause of irreversible vision loss due to retinal ganglion cell (RGC) degeneration that develops slowly with age. Elevated intraocular pressure (IOP) is a significant risk factor, although many patients develop glaucoma with IOP in the normal range. Mutations in microfibril-associated genes cause glaucoma in animal models, suggesting the hypothesis that microfibril defects contribute to glaucoma. To test this hypothesis, we investigated IOP and functional/structural correlates of RGC degeneration in mice of either sex with abnormal microfibrils due to heterozygous Tsk mutation of the fibrilin-1 gene (Fbn1Tsk /+). Although IOP was not affected, Fbn1Tsk /+ mice developed functional deficits at advanced age consistent with glaucoma, including reduced RGC responses in electroretinogram (ERG) experiments. While RGC density in the retina was not affected, the density of RGC axons in the optic nerve was significantly reduced in Fbn1Tsk /+ mice. However, reduced axon density correlated with expanded optic nerves, resulting in similar numbers of axons in Fbn1Tsk /+ and control nerves. Axons in the optic nerves of Fbn1Tsk /+ mice were significantly enlarged and axon diameter was strongly correlated with optic nerve area, as has been reported in early pathogenesis of the DBA/2J mouse model of glaucoma. Our results suggest that microfibril abnormalities can lead to phenotypes found in early-stage glaucomatous neurodegeneration. Thinning of the elastic fiber-rich pia mater was found in Fbn1Tsk /+ mice, suggesting mechanisms allowing for optic nerve expansion and a possible biomechanical contribution to determination of axon caliber.
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PMID:Enlarged Optic Nerve Axons and Reduced Visual Function in Mice with Defective Microfibrils. 3040


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