Publications by authors named "Julie A Wallace"

10 Publications

  • Page 1 of 1

Type 1 Diabetes--Reaping the Rewards of a Targeted Research Investment.

Diabetes 2016 Feb;65(2):307-13

National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.

The Diabetes Control and Complications Trial (DCCT) precipitated a major research effort to develop new approaches to achieve near-normal glycemic control in real-world settings in people with type 1 diabetes. Toward that end, a unique funding stream from the U.S. Congress-the Special Statutory Funding Program for Type 1 Diabetes Research-has provided nearly $2.5 billion for research into the prevention, cure, and treatment of type 1 diabetes since 1998. This funding generated a targeted, sustained investment in type 1 diabetes research with six specific goals: identifying new therapeutic targets through the understanding of disease etiology and pathogenesis, preventing or reversing the disease, developing cell replacement therapy, improving management and care, preventing or reducing the complications, and attracting new talent and applying new technologies to type 1 diabetes research. This Perspective describes exciting results that have emerged from the investment and further advances on the horizon, including artificial pancreas technologies, new therapies for diabetic retinopathy, and breakthroughs in laboratory production of β-cells. The recent program extension enables us to build on this foundation and pursue key new initiatives to harness emerging technologies and develop the next generation of type 1 diabetes researchers.
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http://dx.doi.org/10.2337/db15-1030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876700PMC
February 2016

Cry protein crystals: a novel platform for protein delivery.

PLoS One 2015 1;10(6):e0127669. Epub 2015 Jun 1.

Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, United States of America.

Protein delivery platforms are important tools in the development of novel protein therapeutics and biotechnologies. We have developed a new class of protein delivery agent based on sub-micrometer-sized Cry3Aa protein crystals that naturally form within the bacterium Bacillus thuringiensis. We demonstrate that fusion of the cry3Aa gene to that of various reporter proteins allows for the facile production of Cry3Aa fusion protein crystals for use in subsequent applications. These Cry3Aa fusion protein crystals are efficiently taken up and retained by macrophages and other cell lines in vitro, and can be delivered to mice in vivo via multiple modes of administration. Oral delivery of Cry3Aa fusion protein crystals to C57BL/6 mice leads to their uptake by MHC class II cells, including macrophages in the Peyer's patches, supporting the notion that the Cry3Aa framework can be used to stabilize cargo protein against degradation for delivery to gastrointestinal lymphoid tissues.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0127669PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451076PMC
March 2016

Protein kinase C Beta in the tumor microenvironment promotes mammary tumorigenesis.

Front Oncol 2014 23;4:87. Epub 2014 Apr 23.

Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University , Columbus, OH , USA ; Comprehensive Cancer Center, The Ohio State University , Columbus, OH , USA.

Protein kinase C beta (PKCβ) expression in breast cancer is associated with a more aggressive tumor phenotype, yet the mechanism for how PKCβ is pro-tumorigenic in this disease is still unclear. Interestingly, while it is known that PKCβ mediates angiogenesis, immunity, fibroblast function and adipogenesis, all components of the mammary tumor microenvironment (TME), no study to date has investigated whether stromal PKCβ is functionally relevant in breast cancer. Herein, we evaluate mouse mammary tumor virus-polyoma middle T-antigen (MMTV-PyMT) induced mammary tumorigenesis in the presence and absence of PKCβ. We utilize two model systems: one where PKCβ is deleted in both the epithelial and stromal compartments to test the global requirement for PKCβ on tumor formation, and second, where PKCβ is deleted only in the stromal compartment to test its role in the TME. MMTV-PyMT mice globally lacking PKCβ live longer and develop smaller tumors with decreased proliferation and decreased macrophage infiltration. Similarly, when PKCβ is null exclusively in the stroma, PyMT-driven B6 cells form smaller tumors with diminished collagen deposition. These experiments reveal for the first time a tumor promoting role for stromal PKCβ in MMTV-PyMT tumorigenesis. In corroboration with these results, PKCβ mRNA (Prkcb) is increased in fibroblasts isolated from MMTV-PyMT tumors. These data were confirmed in a breast cancer patient cohort. Combined these data suggest the continued investigation of PKCβ in the mammary TME is necessary to elucidate how to effectively target this signaling pathway in breast cancer.
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http://dx.doi.org/10.3389/fonc.2014.00087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006052PMC
May 2014

Ets2 in tumor fibroblasts promotes angiogenesis in breast cancer.

PLoS One 2013 16;8(8):e71533. Epub 2013 Aug 16.

Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America.

Tumor fibroblasts are active partners in tumor progression, but the genes and pathways that mediate this collaboration are ill-defined. Previous work demonstrates that Ets2 function in stromal cells significantly contributes to breast tumor progression. Conditional mouse models were used to study the function of Ets2 in both mammary stromal fibroblasts and epithelial cells. Conditional inactivation of Ets2 in stromal fibroblasts in PyMT and ErbB2 driven tumors significantly reduced tumor growth, however deletion of Ets2 in epithelial cells in the PyMT model had no significant effect. Analysis of gene expression in fibroblasts revealed a tumor- and Ets2-dependent gene signature that was enriched in genes important for ECM remodeling, cell migration, and angiogenesis in both PyMT and ErbB2 driven-tumors. Consistent with these results, PyMT and ErbB2 tumors lacking Ets2 in fibroblasts had fewer functional blood vessels, and Ets2 in fibroblasts elicited changes in gene expression in tumor endothelial cells consistent with this phenotype. An in vivo angiogenesis assay revealed the ability of Ets2 in fibroblasts to promote blood vessel formation in the absence of tumor cells. Importantly, the Ets2-dependent gene expression signatures from both mouse models were able to distinguish human breast tumor stroma from normal stroma, and correlated with patient outcomes in two whole tumor breast cancer data sets. The data reveals a key function for Ets2 in tumor fibroblasts in signaling to endothelial cells to promote tumor angiogenesis. The results highlight the collaborative networks that orchestrate communication between stromal cells and tumor cells, and suggest that targeting tumor fibroblasts may be an effective strategy for developing novel anti-angiogenic therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071533PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3745457PMC
April 2014

Biomedical research: paving a pathway to diabetes prevention.

Am J Prev Med 2013 Apr;44(4 Suppl 4):S317-23

National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.

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http://dx.doi.org/10.1016/j.amepre.2012.12.017DOI Listing
April 2013

Pten in the breast tumor microenvironment: modeling tumor-stroma coevolution.

Cancer Res 2011 Feb 8;71(4):1203-7. Epub 2011 Feb 8.

Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio, USA.

Solid human tumors and their surrounding microenvironment are hypothesized to coevolve in a manner that promotes tumor growth, invasiveness, and spread. Mouse models of cancer have focused on genetic changes in the epithelial tumor cells and therefore have not robustly tested this hypothesis. We have recently developed a murine breast cancer model that ablates the PTEN tumor suppressor pathway in stromal fibroblasts. Remarkably, the model resembles human breast tumors both at morphologic and molecular levels. We propose that such models reflect subtypes of tumor-stromal coevolution relevant to human breast cancer, and will therefore be useful in defining the mechanisms that underpin tumor-stroma cross-talk. Additionally, these models should also aid in molecularly classifying human breast tumors on the basis of both the microenvironment subtypes they contain as well as on the tumor subtype.
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http://dx.doi.org/10.1158/0008-5472.CAN-10-3263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075554PMC
February 2011

Pten in stromal fibroblasts suppresses mammary epithelial tumours.

Nature 2009 Oct;461(7267):1084-91

Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA.

The tumour stroma is believed to contribute to some of the most malignant characteristics of epithelial tumours. However, signalling between stromal and tumour cells is complex and remains poorly understood. Here we show that the genetic inactivation of Pten in stromal fibroblasts of mouse mammary glands accelerated the initiation, progression and malignant transformation of mammary epithelial tumours. This was associated with the massive remodelling of the extracellular matrix (ECM), innate immune cell infiltration and increased angiogenesis. Loss of Pten in stromal fibroblasts led to increased expression, phosphorylation (T72) and recruitment of Ets2 to target promoters known to be involved in these processes. Remarkably, Ets2 inactivation in Pten stroma-deleted tumours ameliorated disruption of the tumour microenvironment and was sufficient to decrease tumour growth and progression. Global gene expression profiling of mammary stromal cells identified a Pten-specific signature that was highly represented in the tumour stroma of patients with breast cancer. These findings identify the Pten-Ets2 axis as a critical stroma-specific signalling pathway that suppresses mammary epithelial tumours.
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http://dx.doi.org/10.1038/nature08486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2767301PMC
October 2009

We gather together: insulators and genome organization.

Curr Opin Genet Dev 2007 Oct 24;17(5):400-7. Epub 2007 Oct 24.

Laboratory of Molecular Biology, NIDDK, National Institutes of Health, Bethesda, MD 20892-0540, United States.

When placed between an enhancer and promoter, certain DNA sequence elements inhibit enhancer-stimulated gene expression. The best characterized of these enhancer-blocking insulators, gypsy in Drosophila and the CTCF-binding element in vertebrates and flies, stabilize contacts between distant genomic regulatory sites leading to the formation of loop domains. Current results show that CTCF mediates long-range contacts in the mouse beta-globin locus and at the Igf2/H19-imprinted locus. Recently described active chromatin hubs and transcription factories also involve long-range interactions; it is likely that CTCF interferes with their formation when acting as an insulator. The properties of CTCF, and its newly described genomic distribution, suggest that it may play an important role in large-scale nuclear architecture, perhaps mediated by the co-factors with which it interacts in vivo.
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http://dx.doi.org/10.1016/j.gde.2007.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2215060PMC
October 2007

Replication of heterochromatin: insights into mechanisms of epigenetic inheritance.

Chromosoma 2005 Dec 15;114(6):389-402. Epub 2005 Nov 15.

Whitehead Institute, Cambridge, MA, 02142, USA.

Heterochromatin is composed of tightly condensed chromatin in which the histones are deacetylated and methylated, and specific nonhistone proteins are bound. Additionally, in vertebrates and plants, the DNA within heterochromatin is methylated. As the heterochromatic state is stably inherited, replication of heterochromatin requires not only duplication of the DNA but also a reinstallment of the appropriate protein and DNA modifications. Thus replication of heterochromatin provides a framework for understanding mechanisms of epigenetic inheritance. In recent studies, roles have been identified for replication factors in reinstating heterochromatin, particularly functions for origin recognition complex, proliferating cell nuclear antigen, and chromatin-assembly factor 1 in recruiting the heterochromatin binding protein HP1, a histone methyltransferase, a DNA methyltransferase, and a chromatin remodeling complex. Potential mechanistic links between these factors are discussed. In some cells, replication of the heterochromatin is blocked, and in Drosophila this inhibition is mediated by a chromatin binding protein SuUR.
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http://dx.doi.org/10.1007/s00412-005-0024-6DOI Listing
December 2005

The anaphase promoting complex/cyclosome is required during development for modified cell cycles.

Proc Natl Acad Sci U S A 2002 Aug 8;99(17):11217-22. Epub 2002 Aug 8.

Whitehead Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

Animals and plants use modified cell cycles to achieve particular developmental strategies. In one common example, most animals and plants have tissues in which the cells become polyploid or polytene by means of an S-G cycle, but the mechanism by which mitosis is inhibited in the endo cycle is not understood. The Drosophila morula (mr) gene regulates variant cell cycles, because in addition to disrupting the archetypal cycle (G1-S-G2-M), mr mutations affect the rapid embryonic (S-M) divisions as well as the endo cycle (S-G) that produces polyploid cells. In dividing cells mr mutations cause a metaphase arrest, and endo cycling nurse cells inappropriately reenter mitosis in mr mutants. We show mr encodes the APC2 subunit of the anaphase promoting complex/cyclosome. This finding demonstrates that anaphase promoting complex/cyclosome is required not only in proliferating cells but also to block mitosis in some endo cycles. The mr mutants further indicate that transient mitotic functions in endo cycles change chromosome morphology from polytene to polyploid.
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http://dx.doi.org/10.1073/pnas.172391099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC123236PMC
August 2002