The CTSA Consortium's Catalog of Assets for Translational and Clinical Health Research (CATCHR)

The 61 CTSA Consortium sites are home to valuable programs and infrastructure supporting translational science and all are charged with ensuring that such investments translate quickly to improved clinical care. Catalog of Assets for Translational and Clinical Health Research (CATCHR) is the Consortium's effort to collect and make available information on programs and resources to maximize efficiency and facilitate collaborations. By capturing information on a broad range of assets supporting the entire clinical and translational research spectrum, CATCHR aims to provide the necessary infrastructure and processes to establish and maintain an open‐access, searchable database of consortium resources to support multisite clinical and translational research studies. Data are collected using rigorous, defined methods, with the resulting information made visible through an integrated, searchable Web‐based tool. Additional easy‐to‐use Web tools assist resource owners in validating and updating resource information over time. In this paper, we discuss the design and scope of the project, data collection methods, current results, and future plans for development and sustainability. With increasing pressure on research programs to avoid redundancy, CATCHR aims to make available information on programs and core facilities to maximize efficient use of resources.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106893/1/cts12144.pd

The CTSA Consortium's Catalog of Assets for Translational and Clinical Health Research (CATCHR): The Ctsa Consortium's Catchr

The 61 CTSA Consortium sites are home to valuable programs and infrastructure supporting translational science and all are charged with ensuring that such investments translate quickly to improved clinical care. CATCHR (Catalog of Assets for Translational and Clinical Health Research) is the Consortium’s effort to collect and make available information on programs and resources to maximize efficiency and facilitate collaborations. By capturing information on a broad range of assets supporting the entire clinical and translational research spectrum, CATCHR aims to provide the necessary infrastructure and processes to establish and maintain an open-access, searchable database of consortium resources to support multi-site clinical and translational research studies. Data is collected using rigorous, defined methods, with the resulting information made visible through an integrated, searchable web-based tool. Additional easy to use web tools assist resource owners in validating and updating resource information over time. In this article, we discuss the design and scope of the project, data collection methods, current results, and future plans for development and sustainability. With increasing pressure on research programs to avoid redundancy, CATCHR aims to make available information on programs and core facilities to maximize efficient use of resources

Altered mechanisms of signaling and transcription factor regulation in aged B cell development

Senescence in mice is associated with reductions in bone marrow pre-B cells. These follow developmental steps that are critically dependent on signaling through the pre-B cell receptor (preBCR) and the IL-7 receptor. We have categorized a large panel of aged BALB/c mice into two phenotypes based on their patterns of pre-B/pro-B cell loss. Each phenotype is characterized by distinct responses to IL-7 and capacity for survival in vitro. A "moderate" loss of late-stage pre-B cells (25--80%) coincided with decline in signaling responses to IL-7 as well as IL-7 mediated proliferation. A "severe" loss of pre-B cells (>80%) resulted in a reduced pro-B cell pool which retained normal activation and proliferative responses to IL-7, but increased susceptibility to apoptosis. We suggest that aged mice accumulate B cell precursors that are poorly responsive to IL-7 and progressively eliminate them via apoptosis, selecting for B cell precursors that retain the capacity to respond to IL-7.The E2A-encoded E47 protein is critical for the development of B cell precursors. E47 protein levels increase in the pro-B to pre-B cell transition. We show that the rate of E47 protein turnover is increased in the absence of preBCR expression, suggesting that signaling through the preBCR promotes E47 stability.Freshly isolated bone marrow pro-B/early pre-B cells from aged BALB/c mice expressed lower E47 protein levels than young controls. In contrast, the reduced pool of aged late-stage pre-B cells retained normal E47 expression. Cultured senescent pro-B/early pre-B cells exhibited reduced E47 protein levels, DNA-binding activity and stability as compared to young controls, but E2A mRNA levels and turnover were normal. Reduced E47 protein levels were due to increased protein turnover, likely proteasome mediated. We propose that reduced E47 protein levels in aged B cell precursors result from extrinsic, senescence-associated microenvironmental bone marrow alterations and are further aggravated by defects in signaling mediated via the preBCR. Maintenance of normal E47 protein levels within the highly reduced pre-B cell pool in senescence suggests that pre-B cells undergo selection based on E47 expression. Dysregulation of protein turnover likely constitutes a novel and important defect in B lymphopoiesis during senescence.</p

Altered mechanisms of signaling and transcription factor regulation in aged B cell development

Senescence in mice is associated with reductions in bone marrow pre-B cells. These follow developmental steps that are critically dependent on signaling through the pre-B cell receptor (preBCR) and the IL-7 receptor. We have categorized a large panel of aged BALB/c mice into two phenotypes based on their patterns of pre-B/pro-B cell loss. Each phenotype is characterized by distinct responses to IL-7 and capacity for survival in vitro. A moderate loss of late-stage pre-B cells (25--80%) coincided with decline in signaling responses to IL-7 as well as IL-7 mediated proliferation. A severe loss of pre-B cells (\u3e80%) resulted in a reduced pro-B cell pool which retained normal activation and proliferative responses to IL-7, but increased susceptibility to apoptosis. We suggest that aged mice accumulate B cell precursors that are poorly responsive to IL-7 and progressively eliminate them via apoptosis, selecting for B cell precursors that retain the capacity to respond to IL-7.The E2A-encoded E47 protein is critical for the development of B cell precursors. E47 protein levels increase in the pro-B to pre-B cell transition. We show that the rate of E47 protein turnover is increased in the absence of preBCR expression, suggesting that signaling through the preBCR promotes E47 stability.Freshly isolated bone marrow pro-B/early pre-B cells from aged BALB/c mice expressed lower E47 protein levels than young controls. In contrast, the reduced pool of aged late-stage pre-B cells retained normal E47 expression. Cultured senescent pro-B/early pre-B cells exhibited reduced E47 protein levels, DNA-binding activity and stability as compared to young controls, but E2A mRNA levels and turnover were normal. Reduced E47 protein levels were due to increased protein turnover, likely proteasome mediated. We propose that reduced E47 protein levels in aged B cell precursors result from extrinsic, senescence-associated microenvironmental bone marrow alterations and are further aggravated by defects in signaling mediated via the preBCR. Maintenance of normal E47 protein levels within the highly reduced pre-B cell pool in senescence suggests that pre-B cells undergo selection based on E47 expression. Dysregulation of protein turnover likely constitutes a novel and important defect in B lymphopoiesis during senescence

Age-related differences in the E2A-encoded transcription factor E47 in bone marrow-derived B cell precursors and in splenic B cells

We have investigated the effects of aging on the E2A-encoded transcription factor E47, a key regulator of B cell functions, in B cell precursors and in splenic B cells. Here, we show that old mice can be classified as severely depleted, moderately depleted or not depleted mice, according to the percentage of pre-B cells in their bone marrow. IL-7-expanded populations of pro-B/early pre-B cells from bone marrow of both severely depleted and moderately depleted old mice exhibit a reduced E47 DNA-binding and expression compared to young mice, and this defect in severely depleted old mice is more dramatic than that in moderately depleted old mice. However, mRNA levels were comparable, suggesting that E47 in the bone marrow is not transcriptionally regulated. In the spleen, activated B cells from both severely depleted and moderately depleted old mice show a lower E47 DNA-binding and expression than young mice. However, in contrast to precursor B cells, E47 DNA-binding and expression are similarly and only moderately reduced in both severely depleted and in moderately depleted mice. The mRNA levels were found to be decreased in stimulated splenic B cells from old as compared to young mice, suggesting that E47 mRNA in the spleen may be both transcriptionally and/or post-transcriptionally regulated

Reduced Ig class switch in aged mice correlates with decreased E47 and activation-induced cytidine deaminase

The capacity to class switch the IgH chain is critical to the effectiveness of humoral immune responses. We show that in vitro-stimulated splenic B cells from senescent mice are deficient in production of multiple class switch isotypes (IgG1, G2a, G3, and E), class switch recombination (CSR), and induction of the E2A-encoded transcription factor E47. E47 has previously been shown to be required for CSR, at least in part via expression of the activation-induced cytidine deaminase. Our studies show that impaired induction of E47, and subsequently activation-induced cytidine deaminase, contribute to poor CSR and production of secondary isotypes in senescence

Accelerated Notch-dependent degradation of E47 proteins in aged B cell precursors is associated with increased ERK MAPK activation

The transcriptional regulator E47, encoded by the E2A gene, is crucial to B lymphopoiesis. In BALB/c senescent mice (approximately 2 years old), the incidence of E47-expressing pro-B cells in vivo and E47 protein steady state levels in B cell precursors in vitro were reduced. Poor expression of E47 protein was a consequence of accelerated proteasome-mediated turnover and was associated with heightened ubiquitin modification of E2A-encoded proteins in aged B cell precursors. Both MAPK and Notch activity have been previously associated with E2A-encoded protein stability in lymphocytes. Aged B cell precursors exhibited heightened levels of MAPK activity reflected in increased levels of phospho-ERK proteins. Phosphorylation of E2A-encoded proteins was also increased in aged B cell precursors and pharmacologic inhibition of MEK-1 resulted in a partial restoration of their E47 protein. Both Notch proteins and their Delta-like ligands were detected comparably in young and aged B cell precursors. Either inhibition of Notch activation via gamma-secretase or Ab blockade of Notch-Delta-like ligand interactions partially restored E47 expression in aged B cell precursors. We hypothesize that increased MAPK activity promotes phosphorylation of E2A-encoded protein in aged B cell precursors. Subsequently, E2A-encoded proteins undergo ubiquitination and accelerated degradation in a Notch-dependent process. The dysregulation of E2A-encoded protein expression may contribute to the reductions seen in early B lymphopoiesis during murine senescence

Aged mice exhibit distinct B cell precursor phenotypes differing in activation, proliferation and apoptosis

Senescence in murine models is associated with a reduction, albeit heterogeneous, in bone marrow pre-B cells. We have categorized aged BALB/c mice into two phenotypes based on their patterns of pre-B/pro-B cell loss. Each phenotype is characterized by distinct responses to the growth cytokine IL-7 and capacity for survival in vitro. A 'moderate' loss of late-stage pre-B cells (25-80%) coincided with decline in proliferation to rmIL-7. This was also associated with a decrease in the frequency of pro-B cells which increased phosphotyrosine content upon IL-7 stimulation, an indicator of early activation events. A 'severe' loss of pre-B cells (>80%) resulted in a reduced pro-B cell pool which retained normal activation and proliferative responses to IL-7. B cell precursors from aged mice with severe alterations in B lymphopoiesis displayed increased susceptibility to apoptosis in comparison to both aged mice with moderate B cell precursor loss and young mice. Conceivably, during senescence, aged mice may initially accumulate B cell precursors which are poorly responsive to IL-7. Progressively, these refractory B cell precursors may be eliminated via apoptosis; however, the remaining limited pool of B cell precursors retains the capacity to respond to IL-7 stimulation