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Transcriptomic Data Mining and Repurposing for Computational Drug Discovery.

Fri, 2018-12-14 15:42
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Transcriptomic Data Mining and Repurposing for Computational Drug Discovery.

Methods Mol Biol. 2019;1903:73-95

Authors: Wang Y, Yella J, Jegga AG

Abstract
Conventional drug discovery in general is costly and time-consuming with extremely low success and relatively high attrition rates. The disparity between high cost of drug discovery and vast unmet medical needs resulted in advent of an increasing number of computational approaches that can "connect" disease with a candidate therapeutic. This includes computational drug repurposing or repositioning wherein the goal is to discover a new indication for an approved drug. Computational drug discovery approaches that are commonly used are similarity-based wherein network analysis or machine learning-based methods are used. One such approach is matching gene expression signatures from disease to those from small molecules, commonly referred to as connectivity mapping. In this chapter, we will focus on how publicly available existing transcriptomic data from diseases can be reused to identify novel candidate therapeutics and drug repositioning candidates. To elucidate these, we will present two case studies: (1) using transcriptional signature similarity or positive correlation to identify novel small molecules that are similar to an approved drug and (2) identifying candidate therapeutics via reciprocal connectivity or negative correlation between transcriptional signatures from a disease and small molecule.

PMID: 30547437 [PubMed - in process]

Wilms' tumor 1 drives fibroproliferation and myofibroblast transformation in severe fibrotic lung disease.

Fri, 2018-08-24 08:27
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Wilms' tumor 1 drives fibroproliferation and myofibroblast transformation in severe fibrotic lung disease.

JCI Insight. 2018 Aug 23;3(16):

Authors: Sontake V, Kasam RK, Sinner D, Korfhagen TR, Reddy GB, White ES, Jegga AG, Madala SK

Abstract
Wilms' tumor 1 (WT1) is a critical transcriptional regulator of mesothelial cells during lung development but is downregulated in postnatal stages and adult lungs. We recently showed that WT1 is upregulated in both mesothelial cells and mesenchymal cells in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal fibrotic lung disease. Although WT1-positive cell accumulation leading to severe fibrotic lung disease has been studied, the role of WT1 in fibroblast activation and pulmonary fibrosis remains elusive. Here, we show that WT1 functions as a positive regulator of fibroblast activation, including fibroproliferation, myofibroblast transformation, and extracellular matrix (ECM) production. Chromatin immunoprecipitation experiments indicate that WT1 binds directly to the promoter DNA sequence of α-smooth muscle actin (αSMA) to induce myofibroblast transformation. In support, the genetic lineage tracing identifies WT1 as a key driver of mesothelial-to-myofibroblast and fibroblast-to-myofibroblast transformation. Importantly, the partial loss of WT1 was sufficient to attenuate myofibroblast accumulation and pulmonary fibrosis in vivo. Further, our coculture studies show that WT1 upregulation leads to non-cell autonomous effects on neighboring cells. Thus, our data uncovered a pathogenic role of WT1 in IPF by promoting fibroblast activation in the peripheral areas of the lung and as a target for therapeutic intervention.

PMID: 30135315 [PubMed - as supplied by publisher]

Chromatin-associated APC regulates gene expression in collaboration with canonical WNT signaling and AP-1.

Thu, 2018-08-23 07:57
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Chromatin-associated APC regulates gene expression in collaboration with canonical WNT signaling and AP-1.

Oncotarget. 2018 Jul 27;9(58):31214-31230

Authors: Hankey W, Chen Z, Bergman MJ, Fernandez MO, Hancioglu B, Lan X, Jegga AG, Zhang J, Jin VX, Aronow BJ, Wang Q, Groden J

Abstract
Mutation of the APC gene occurs in a high percentage of colorectal tumors and is a central event driving tumor initiation in the large intestine. The APC protein performs multiple tumor suppressor functions including negative regulation of the canonical WNT signaling pathway by both cytoplasmic and nuclear mechanisms. Published reports that APC interacts with β-catenin in the chromatin fraction to repress WNT-activated targets have raised the possibility that chromatin-associated APC participates more broadly in mechanisms of transcriptional control. This screening study has used chromatin immunoprecipitation and next-generation sequencing to identify APC-associated genomic regions in colon cancer cell lines. Initial target selection was performed by comparison and statistical analysis of 3,985 genomic regions associated with the APC protein to whole transcriptome sequencing data from APC-deficient and APC-wild-type colon cancer cells, and two types of murine colon adenomas characterized by activated Wnt signaling. 289 transcripts altered in expression following APC loss in human cells were linked to APC-associated genomic regions. High-confidence targets additionally validated in mouse adenomas included 16 increased and 9 decreased in expression following APC loss, indicating that chromatin-associated APC may antagonize canonical WNT signaling at both WNT-activated and WNT-repressed targets. Motif analysis and comparison to ChIP-seq datasets for other transcription factors identified a prevalence of binding sites for the TCF7L2 and AP-1 transcription factors in APC-associated genomic regions. Our results indicate that canonical WNT signaling can collaborate with or antagonize the AP-1 transcription factor to fine-tune the expression of shared target genes in the colorectal epithelium. Future therapeutic strategies for APC-deficient colorectal cancers might be expanded to include agents targeting the AP-1 pathway.

PMID: 30131849 [PubMed]

An Hsp20-FBXO4 Axis Regulates Adipocyte Function through Modulating PPARγ Ubiquitination.

Thu, 2018-06-21 06:32

An Hsp20-FBXO4 Axis Regulates Adipocyte Function through Modulating PPARγ Ubiquitination.

Cell Rep. 2018 Jun 19;23(12):3607-3620

Authors: Peng J, Li Y, Wang X, Deng S, Holland J, Yates E, Chen J, Gu H, Essandoh K, Mu X, Wang B, McNamara RK, Peng T, Jegga AG, Liu T, Nakamura T, Huang K, Perez-Tilve D, Fan GC

Abstract
Exposure to cold temperature is well known to upregulate heat shock protein (Hsp) expression and recruit and/or activate brown adipose tissue and beige adipocytes in humans and animals. However, whether and how Hsps regulate adipocyte function for energy homeostatic responses is poorly understood. Here, we demonstrate a critical role of Hsp20 as a negative regulator of adipocyte function. Deletion of Hsp20 enhances non-shivering thermogenesis and suppresses inflammatory responses, leading to improvement of glucose and lipid metabolism under both chow diet and high-fat diet conditions. Mechanistically, Hsp20 controls adipocyte function by interacting with the subunit of the ubiquitin ligase complex, F-box only protein 4 (FBXO4), and regulating the ubiquitin-dependent degradation of peroxisome proliferation activated receptor gamma (PPARγ). Indeed, Hsp20 deficiency mimics and enhances the pharmacological effects of the PPARγ agonist rosiglitazone. Together, our findings suggest a role of Hsp20 in mediating adipocyte function by linking β-adrenergic signaling to PPARγ activity.

PMID: 29925002 [PubMed - in process]

Novel phenotype-disease matching tool for rare genetic diseases.

Thu, 2018-06-14 06:22
Related Articles

Novel phenotype-disease matching tool for rare genetic diseases.

Genet Med. 2018 Jun 12;:

Authors: Chen J, Xu H, Jegga A, Zhang K, White PS, Zhang G

Abstract
PURPOSE: To improve the accuracy of matching rare genetic diseases based on patient's phenotypes.
METHODS: We introduce new methods to prioritize diagnosis of genetic diseases based on integrated semantic similarity (method 1) and ontological overlap (method 2) between the phenotypes expressed by a patient and phenotypes annotated to known diseases.
RESULTS: We evaluated the performance of our methods by two sets of simulated data and one set of patient's data derived from electronic health records. We demonstrated that the two methods achieved significantly improved performance compared with previous methods in correctly prioritizing candidate diseases in all of the three sets. Our methods are freely available as a web application ( https://gddp.
RESEARCH: cchmc.org/ ) to aid diagnosis of genetic diseases.
CONCLUSION: Our methods can capture the diagnostic information embedded in the phenotype ontology, consider all phenotypes exhibited by a patient, and are more robust than the existing methods when phenotypes are incorrectly or imprecisely specified. These methods can assist the diagnosis of rare genetic diseases and help the interpretation of the results of DNA tests.

PMID: 29895857 [PubMed - as supplied by publisher]

GNOMICS: A one-stop shop for biomedical and genomic data.

Tue, 2018-06-12 08:32

GNOMICS: A one-stop shop for biomedical and genomic data.

AMIA Jt Summits Transl Sci Proc. 2018;2017:118-123

Authors: Kronk CJ, Jegga A

Abstract
The World Wide Web is an indispensable tool for biomedical researchers who are striving to understand the molecular basis of phenotype. However, it presents challenges in the form of proliferation of data resources, with heterogeneity ranging from their content to functionality to interfaces. This often frustrates researchers who must visit multiple sites, become familiar with their interfaces, and learn how to use them to extract knowledge. Even then, one may never feel sure that they have tracked down all needed information. We envision addressing this challenge with GNOMICS (Genomic Nomenclature Omnibus and Multifaceted Informatics and Computational Suite), a suite with both a programmatic interface and a GUI. GNOMICS allows for extensible biomedical functionality, including identifier conversion, pathway enrichment, sequence alignment, and reference gathering, among others. It combines usage of other biological and chemical database application programming interfaces (APIs) to deliver uniform data which can be further manipulated and parsed.

PMID: 29888054 [PubMed]

Characterizing drug-related adverse events by joint analysis of biomedical and genomic data: A case study of drug-induced pulmonary fibrosis.

Tue, 2018-06-12 08:32

Characterizing drug-related adverse events by joint analysis of biomedical and genomic data: A case study of drug-induced pulmonary fibrosis.

AMIA Jt Summits Transl Sci Proc. 2018;2017:91-97

Authors: Jiang A, Jegga AG

Abstract
Spontaneous reporting systems such as the FDA's adverse event reporting system (FAERS) present a great resource to mine for and analyze real-world medication usage. Our study is based on a central premise that FAERS captures unsuspected drug-related adverse events (AEs). Since drug-related AEs result for several reasons, no single approach will be able to predict the entire gamut of AEs. A fundamental premise of systems biology is that a full understanding of a biological process or phenotype (e.g., drug-related AE) requires that all the individual elements be studied in conjunction with one another. We therefore hypothesize that integrative analysis of FAERS-based drug-related AEs with the transcriptional signatures from disease models and drug treatments can lead to the generation of unbiased hypotheses for drug-induced AE-modulating mechanisms of action as well as drug combinations that may target those mechanisms. We test this hypothesis using drug-induced pulmonary fibrosis (DIPF) as a proof-of-concept study.

PMID: 29888048 [PubMed]

Changing Trends in Computational Drug Repositioning.

Fri, 2018-06-08 06:42
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Changing Trends in Computational Drug Repositioning.

Pharmaceuticals (Basel). 2018 Jun 05;11(2):

Authors: Yella JK, Yaddanapudi S, Wang Y, Jegga AG

Abstract
Efforts to maximize the indications potential and revenue from drugs that are already marketed are largely motivated by what Sir James Black, a Nobel Prize-winning pharmacologist advocated-"The most fruitful basis for the discovery of a new drug is to start with an old drug". However, rational design of drug mixtures poses formidable challenges because of the lack of or limited information about in vivo cell regulation, mechanisms of genetic pathway activation, and in vivo pathway interactions. Hence, most of the successfully repositioned drugs are the result of "serendipity", discovered during late phase clinical studies of unexpected but beneficial findings. The connections between drug candidates and their potential adverse drug reactions or new applications are often difficult to foresee because the underlying mechanism associating them is largely unknown, complex, or dispersed and buried in silos of information. Discovery of such multi-domain pharmacomodules-pharmacologically relevant sub-networks of biomolecules and/or pathways-from collection of databases by independent/simultaneous mining of multiple datasets is an active area of research. Here, while presenting some of the promising bioinformatics approaches and pipelines, we summarize and discuss the current and evolving landscape of computational drug repositioning.

PMID: 29874824 [PubMed]

The nuclear DEK interactome supports multi-functionality: "The DEK Interactome".

Tue, 2017-10-31 06:12

The nuclear DEK interactome supports multi-functionality: "The DEK Interactome".

Proteins. 2017 Oct 30;:

Authors: Smith EA, Krumpelbeck EF, Jegga AG, Prell M, Matrka MM, Kappes F, Greis KD, Ali AM, Meetei AR, Wells SI

Abstract
DEK is an oncoprotein that is overexpressed in many forms of cancer and participates in numerous cellular pathways. Of these different pathways, relevant interacting partners and functions of DEK are well described in regard to the regulation of chromatin structure, epigenetic marks, and transcription. Most of this understanding was derived by investigating DNA-binding and chromatin processing capabilities of the oncoprotein. To facilitate the generation of mechanism-driven hypotheses regarding DEK activities in underexplored areas, we have developed the first DEK interactome model using tandem-affinity purification and mass spectrometry. With this approach we identify IMPDH2, DDX21, and RPL7a as novel DEK binding partners, hinting at new roles for the oncogene in de novo nucleotide biosynthesis and ribosome formation. Additionally, a hydroxyurea-specific interaction with RPA was observed, suggesting that a DEK-RPA complex may form in response to DNA replication fork stalling. Taken together, these findings highlight diverse activities for DEK across cellular pathways and support a model wherein this molecule performs a plethora of functions. This article is protected by copyright. All rights reserved.

PMID: 29082557 [PubMed - as supplied by publisher]

Unsupervised gene expression analyses identify IPF-severity correlated signatures, associated genes and biomarkers.

Tue, 2017-10-24 08:50

Unsupervised gene expression analyses identify IPF-severity correlated signatures, associated genes and biomarkers.

BMC Pulm Med. 2017 Oct 20;17(1):133

Authors: Wang Y, Yella J, Chen J, McCormack FX, Madala SK, Jegga AG

Abstract
BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a fatal fibrotic lung disease occurring predominantly in middle-aged and older adults. The traditional diagnostic classification of IPF is based on clinical, radiological, and histopathological features. However, the considerable heterogeneity in IPF presentation suggests that differences in gene expression profiles can help to characterize and distinguish disease severity.
METHODS: We used data-driven unsupervised clustering analysis, combined with a knowledge-based approach to identify and characterize IPF subgroups.
RESULTS: Using transcriptional profiles on lung tissue from 131 patients with IPF/UIP and 12 non-diseased controls, we identified six subgroups of IPF that generally correlated with the disease severity and lung function decline. Network-informed clustering identified the most severe subgroup of IPF that was enriched with genes regulating inflammatory processes, blood pressure and branching morphogenesis of the lung. The differentially expressed genes in six subgroups of IPF compared to healthy control include transcripts of extracellular matrix, epithelial-mesenchymal cell cross-talk, calcium ion homeostasis, and oxygen transport. Further, we compiled differentially expressed gene signatures to identify unique gene clusters that can segregate IPF from normal, and severe from mild IPF. Additional validations of these signatures were carried out in three independent cohorts of IPF/UIP. Finally, using knowledge-based approaches, we identified several novel candidate genes which may also serve as potential biomarkers of IPF.
CONCLUSIONS: Discovery of unique and redundant gene signatures for subgroups in IPF can be greatly facilitated through unsupervised clustering. Findings derived from such gene signatures may provide insights into pathogenesis of IPF and facilitate the development of clinically useful biomarkers.

PMID: 29058630 [PubMed - in process]

Gene-disease associations identify a connectome with shared molecular pathways in human cholangiopathies.

Sun, 2017-09-03 07:23

Gene-disease associations identify a connectome with shared molecular pathways in human cholangiopathies.

Hepatology. 2017 Sep 02;:

Authors: Luo Z, Jegga AG, Bezerra JA

Abstract
Cholangiopathies are a diverse group of progressive diseases whose primary cell targets are cholangiocytes. To identify shared pathogenesis and molecular connectivity among the three main human cholangiopathies (biliary atresia [BA], primary biliary cholangitis [PBC] and primary sclerosing cholangitis [PSC]), we built a comprehensive platform of published data on gene variants, gene expression and functional studies, and applied network-based analytics in search for shared molecular circuits. Mining the data platform with largest connected component and interactome analyses, we validated previously reported associations and identified essential- and hub-genes. In addition to disease-specific modules, we found a substantial overlap of disease neighborhoods, and uncovered a group of 34 core genes that are enriched for immune processes and abnormal intestine/hepatobiliary mouse phenotypes. Within this core, we identified a gene subcore containing STAT3, IL6, TNF and FOXP3 prominently placed in a regulatory connectome of genes related to cellular immunity and fibrosis. We also found substantial gene enrichment in the AGE-RAGE pathway, and showed that RAGE activation induced cholangiocyte proliferation.
CONCLUSION: Human cholangiopathies share pathways enriched by immunity genes and a molecular connectome that links different pathogenic features of BA, PBC and PSC. This article is protected by copyright. All rights reserved.

PMID: 28865156 [PubMed - as supplied by publisher]

Proteomic Alterations Associated with Biomechanical Dysfunction are Early Processes in the Emilin1 Deficient Mouse Model of Aortic Valve Disease.

Thu, 2017-08-17 11:17
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Proteomic Alterations Associated with Biomechanical Dysfunction are Early Processes in the Emilin1 Deficient Mouse Model of Aortic Valve Disease.

Ann Biomed Eng. 2017 Aug 15;:

Authors: Angel PM, Narmoneva DA, Sewell-Loftin MK, Munjal C, Dupuis L, Landis BJ, Jegga A, Kern CB, Merryman WD, Baldwin HS, Bressan GM, Hinton RB

Abstract
Aortic valve (AV) disease involves stiffening of the AV cusp with progression characterized by inflammation, fibrosis, and calcification. Here, we examine the relationship between biomechanical valve function and proteomic changes before and after the development of AV pathology in the Emilin1-/- mouse model of latent AV disease. Biomechanical studies were performed to quantify tissue stiffness at the macro (micropipette) and micro (atomic force microscopy (AFM)) levels. Micropipette studies showed that the Emilin1-/- AV annulus and cusp regions demonstrated increased stiffness only after the onset of AV disease. AFM studies showed that the Emilin1-/- cusp stiffens before the onset of AV disease and worsens with the onset of disease. Proteomes from AV cusps were investigated to identify protein functions, pathways, and interaction network alterations that occur with age- and genotype-related valve stiffening. Protein alterations due to Emilin1 deficiency, including changes in pathways and functions, preceded biomechanical aberrations, resulting in marked depletion of extracellular matrix (ECM) proteins interacting with TGFB1, including latent transforming growth factor beta 3 (LTBP3), fibulin 5 (FBLN5), and cartilage intermediate layer protein 1 (CILP1). This study identifies proteomic dysregulation is associated with biomechanical dysfunction as early pathogenic processes in the Emilin1-/- model of AV disease.

PMID: 28812215 [PubMed - as supplied by publisher]

Generating testable hypotheses for schizophrenia and rheumatoid arthritis pathogenesis by integrating epidemiological, genomic, and protein interaction data.

Thu, 2017-06-01 07:59
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Generating testable hypotheses for schizophrenia and rheumatoid arthritis pathogenesis by integrating epidemiological, genomic, and protein interaction data.

NPJ Schizophr. 2017;3:11

Authors: Malavia TA, Chaparala S, Wood J, Chowdari K, Prasad KM, McClain L, Jegga AG, Ganapathiraju MK, Nimgaonkar VL

Abstract
Patients with schizophrenia and their relatives have reduced prevalence of rheumatoid arthritis. Schizophrenia and rheumatoid arthritis genome-wide association studies also indicate negative genetic correlations, suggesting that there may be shared pathogenesis at the DNA level or downstream. A portion of the inverse prevalence could be attributed to pleiotropy, i.e., variants of a single nucleotide polymorphism that could confer differential risk for these disorders. To study the basis for such an interrelationship, we initially compared lists of single nucleotide polymorphisms with significant genetic associations (p < 1(e-8)) for schizophrenia or rheumatoid arthritis, evaluating patterns of linkage disequilibrium and apparent pleiotropic risk profiles. Single nucleotide polymorphisms that conferred risk for both schizophrenia and rheumatoid arthritis were localized solely to the extended HLA region. Among single nucleotide polymorphisms that conferred differential risk for schizophrenia and rheumatoid arthritis, the majority were localized to HLA-B, TNXB, NOTCH4, HLA-C, HCP5, MICB, PSORS1C1, and C6orf10; published functional data indicate that HLA-B and HLA-C have the most plausible pathogenic roles in both disorders. Interactomes of these eight genes were constructed from protein-protein interaction information using publicly available databases and novel computational predictions. The genes harboring apparently pleiotropic single nucleotide polymorphisms are closely connected to rheumatoid arthritis and schizophrenia associated genes through common interacting partners. A separate and independent analysis of the interactomes of rheumatoid arthritis and schizophrenia genes showed a significant overlap between the two interactomes and that they share several common pathways, motivating functional studies suggesting a relationship in the pathogenesis of schizophrenia/rheumatoid arthritis.

PMID: 28560257 [PubMed - in process]

Exome Sequencing Identifies Candidate Genetic Modifiers of Syndromic and Familial Thoracic Aortic Aneurysm Severity.

Sun, 2017-05-28 08:47
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Exome Sequencing Identifies Candidate Genetic Modifiers of Syndromic and Familial Thoracic Aortic Aneurysm Severity.

J Cardiovasc Transl Res. 2017 May 26;:

Authors: Landis BJ, Schubert JA, Lai D, Jegga AG, Shikany AR, Foroud T, Ware SM, Hinton RB

Abstract
Thoracic aortic aneurysm (TAA) is a genetic disease predisposing to aortic dissection. It is important to identify the genetic modifiers controlling penetrance and expressivity to improve clinical prognostication. Exome sequencing was performed in 27 subjects with syndromic or familial TAA presenting with extreme phenotypes (15 with severe TAA; 12 with mild or absent TAA). Family-based analysis of a subset of the cohort identified variants, genes, and pathways segregating with TAA severity among three families. A rare missense variant in ADCK4 (p.Arg63Trp) segregated with mild TAA in each family. Genes and pathways identified in families were further investigated in the entire cohort using the optimal unified sequence kernel association test, finding significance for the gene COL15A1 (p = 0.025) and the retina homeostasis pathway (p = 0.035). Thus, we identified candidate genetic modifiers of TAA severity by exome-based study of extreme phenotypes, which may lead to improved risk stratification and development of new medical therapies.

PMID: 28550590 [PubMed - as supplied by publisher]

DEK is required for homologous recombination repair of DNA breaks.

Tue, 2017-03-21 10:32
Related Articles

DEK is required for homologous recombination repair of DNA breaks.

Sci Rep. 2017 Mar 20;7:44662

Authors: Smith EA, Gole B, Willis NA, Soria R, Starnes LM, Krumpelbeck EF, Jegga AG, Ali AM, Guo H, Meetei AR, Andreassen PR, Kappes F, Vinnedge LM, Daniel JA, Scully R, Wiesmüller L, Wells SI

Abstract
DEK is a highly conserved chromatin-bound protein whose upregulation across cancer types correlates with genotoxic therapy resistance. Loss of DEK induces genome instability and sensitizes cells to DNA double strand breaks (DSBs), suggesting defects in DNA repair. While these DEK-deficiency phenotypes were thought to arise from a moderate attenuation of non-homologous end joining (NHEJ) repair, the role of DEK in DNA repair remains incompletely understood. We present new evidence demonstrating the observed decrease in NHEJ is insufficient to impact immunoglobulin class switching in DEK knockout mice. Furthermore, DEK knockout cells were sensitive to apoptosis with NHEJ inhibition. Thus, we hypothesized DEK plays additional roles in homologous recombination (HR). Using episomal and integrated reporters, we demonstrate that HR repair of conventional DSBs is severely compromised in DEK-deficient cells. To define responsible mechanisms, we tested the role of DEK in the HR repair cascade. DEK-deficient cells were impaired for γH2AX phosphorylation and attenuated for RAD51 filament formation. Additionally, DEK formed a complex with RAD51, but not BRCA1, suggesting a potential role regarding RAD51 filament formation, stability, or function. These findings define DEK as an important and multifunctional mediator of HR, and establish a synthetic lethal relationship between DEK loss and NHEJ inhibition.

PMID: 28317934 [PubMed - in process]

Applying systems biology methodology to identify genetic factors possibly associated with recovery after traumatic brain injury.

Sat, 2017-03-18 08:57
Related Articles

Applying systems biology methodology to identify genetic factors possibly associated with recovery after traumatic brain injury.

J Neurotrauma. 2017 Mar 16;:

Authors: Kurowski BG, Treble-Barna A, Pitzer AJ, Wade SL, Martin LJ, Chima RS, Jegga A

Abstract
Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality worldwide. It is linked with a number of medical, neurological, cognitive, and behavioral sequelae. The influence of genetic factors on the biology and related recovery after TBI is poorly understood. Studies that seek to elucidate the impact of genetic influences on neurorecovery after TBI will lead to better individualization of prognosis and inform development of novel treatments, which are considerably lacking. Current genetic studies related to TBI have focused on specific candidate genes. The objectives of this study were to use a system biology-based approach to identify biologic processes over-represented with genetic variants previously implicated in clinical outcomes after TBI and identify unique genes potentially related to recovery after TBI. After performing a systematic review to identify genes in the literature associated with clinical outcomes, we used the genes identified to perform a systems biology-based integrative computational analysis to ascertain the interactions between molecular components and to develop models for regulation and function of genes involved in TBI recovery. The analysis identified over-representation of genetic variants primarily in two biologic processes: response to injury (cell proliferation, cell death, inflammatory response, cellular metabolism) and neurocognitive and behavioral reserve (brain development, cognition, and behavior). Overall this study demonstrates the use of a systems biology-based approach to identify unique/novel genes or sets of genes important to the recovery process. Findings from this systems biology-based approach provide additional insight into the potential impact of genetic variants on the underlying complex biological processes important to TBI recovery and may inform the development of empirical genetic-related studies for TBI. Future studies that combine systems biology methodology and genomic, proteomic, and epigenetic approaches are needed in TBI.

PMID: 28301983 [PubMed - as supplied by publisher]

Inhibition of MAPK-Erk pathway in vivo attenuates aortic valve disease processes in Emilin1-deficient mouse model.

Thu, 2017-03-09 06:17
Related Articles

Inhibition of MAPK-Erk pathway in vivo attenuates aortic valve disease processes in Emilin1-deficient mouse model.

Physiol Rep. 2017 Mar;5(5):

Authors: Munjal C, Jegga AG, Opoka AM, Stoilov I, Norris RA, Thomas CJ, Smith JM, Mecham RP, Bressan GM, Hinton RB

Abstract
Aortic valve disease (AVD) is a common condition with a progressive natural history, and presently, there are no pharmacologic treatment strategies. Elastic fiber fragmentation (EFF) is a hallmark of AVD, and increasing evidence implicates developmental elastic fiber assembly defects. Emilin1 is a glycoprotein necessary for elastic fiber assembly that is present in both developing and mature human and mouse aortic valves. The Emilin1-deficient mouse (Emilin1(-/-) ) is a model of latent AVD, characterized by activated TGFβ/MEK/p-Erk signaling and upregulated elastase activity. Emilin1(-/-) aortic valves demonstrate early EFF and aberrant angiogenesis followed by late neovascularization and fibrosis. The objective of this study was to test the effectiveness of three different targeted therapies. Aged (12-14 months) Emilin1(-/-) mice were treated with refametinib (RDEA-119, MEK1/2 inhibitor), doxycycline (elastase inhibitor), or G6-31 (anti-VEGF-A mouse antibody) for 4 weeks. Refametinib- and doxycycline-treated Emilin1(-/-) mice markedly reduced MEK/p-Erk activation in valve tissue. Furthermore, both refametinib and doxycycline attenuated elastolytic cathepsin K, L, MMP-2, and MMP-9 activation, and abrogated macrophage and neutrophil infiltration in Emilin1(-/-) aortic valves. RNAseq analysis was performed in aortic valve tissue from adult (4 months) and aged (14 months) Emilin1(-/-) and age-matched wild-type control mice, and demonstrated upregulation of genes associated with MAPK/MEK/p-Erk signaling and elastases at the adult stage and inflammatory pathways at the aged stage controlling for age. These results suggest that Erk1/2 signaling is an important modulator of early elastase activation, and pharmacological inhibition using refametinib may be a promising treatment to halt AVD progression.

PMID: 28270590 [PubMed - in process]

Hsp90 regulation of fibroblast activation in pulmonary fibrosis.

Tue, 2017-02-28 06:26
Related Articles

Hsp90 regulation of fibroblast activation in pulmonary fibrosis.

JCI Insight. 2017 Feb 23;2(4):e91454

Authors: Sontake V, Wang Y, Kasam RK, Sinner D, Reddy GB, Naren AP, McCormack FX, White ES, Jegga AG, Madala SK

Abstract
Idiopathic pulmonary fibrosis (IPF) is a severe fibrotic lung disease associated with fibroblast activation that includes excessive proliferation, tissue invasiveness, myofibroblast transformation, and extracellular matrix (ECM) production. To identify inhibitors that can attenuate fibroblast activation, we queried IPF gene signatures against a library of small-molecule-induced gene-expression profiles and identified Hsp90 inhibitors as potential therapeutic agents that can suppress fibroblast activation in IPF. Although Hsp90 is a molecular chaperone that regulates multiple processes involved in fibroblast activation, it has not been previously proposed as a molecular target in IPF. Here, we found elevated Hsp90 staining in lung biopsies of patients with IPF. Notably, fibroblasts isolated from fibrotic lesions showed heightened Hsp90 ATPase activity compared with normal fibroblasts. 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), a small-molecule inhibitor of Hsp90 ATPase activity, attenuated fibroblast activation and also TGF-β-driven effects on fibroblast to myofibroblast transformation. The loss of the Hsp90AB, but not the Hsp90AA isoform, resulted in reduced fibroblast proliferation, myofibroblast transformation, and ECM production. Finally, in vivo therapy with 17-AAG attenuated progression of established and ongoing fibrosis in a mouse model of pulmonary fibrosis, suggesting that targeting Hsp90 represents an effective strategy for the treatment of fibrotic lung disease.

PMID: 28239659 [PubMed - in process]

Correction: IL-31-Driven Skin Remodeling Involves Epidermal Cell Proliferation and Thickening That Lead to Impaired Skin-Barrier Function.

Tue, 2017-01-24 06:21

Correction: IL-31-Driven Skin Remodeling Involves Epidermal Cell Proliferation and Thickening That Lead to Impaired Skin-Barrier Function.

PLoS One. 2017;12(1):e0170446

Authors: Singh B, Jegga AG, Shanmukhappa KS, Edukulla R, Khurana Hershey GK, Medvedovic M, Dillon SR, Madala SK

Abstract
[This corrects the article DOI: 10.1371/journal.pone.0161877.].

PMID: 28114322 [PubMed - in process]

Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation.

Thu, 2016-12-15 16:05
Related Articles

Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation.

J Mol Cell Cardiol. 2016 Dec 09;:

Authors: Lynch TL, Ismahil MA, Jegga AG, Zilliox MJ, Troidl C, Prabhu SD, Sadayappan S

Abstract
Cardiomyopathies are a leading cause of heart failure and are often caused by mutations in sarcomeric genes, resulting in contractile dysfunction and cellular damage. This may stimulate the production of a robust proinflammatory response. To determine whether myocardial inflammation is associated with cardiac dysfunction in dilated cardiomyopathy (DCM) caused by MYBPC3 mutation, we used the well-characterized cMyBP-C((t/t)) mouse model of DCM at 3months of age. Compared to wild type (WT) mice, DCM mice exhibited significantly decreased fractional shortening (36.4±2% vs. 15.5±1.0%, p<0.0001) and significantly increased spleen weight (5.3±0.3% vs. 7.2±0.4mm/mg, p=0.002). Intriguingly, flow cytometry analysis revealed a significant increase in total (CD45(+)CD11b(+)Ly6C(-)MHCII(+)F480(+)) macrophages (6.5±1.4% vs. 14.8±1.4%, p=0.002) and classically activated (CD45(+)CD11b(+)Ly6C(-)MHCII(+)F480(+)CD206(-)) proinflammatory (M1) macrophages (3.4±0.8% vs. 10.3±1.2%, p=0.0009) in DCM hearts as compared with WT hearts. These results were further confirmed by immunofluorescence analysis of heart tissue sections. Splenic red pulp (CD11b(+)Ly6C(+)MHCII(low)F480(hi)) macrophages were significantly elevated (2.4±0.1% vs. 1.3±0.1%, p=0.0001) in DCM compared to WT animals. Serum cytokine analysis in DCM animals exhibited a significant increase (0.65±0.2 vs. 2.175±0.5pg/mL, p=0.02) in interleukin (IL)-6 compared to WT animals. Furthermore, RNA-seq analysis revealed the upregulation of inflammatory pathways in the DCM hearts. Together, these data indicate a robust proinflammatory response in DCM hearts, likely in response to cellular damage triggered by MYBPC3 mutation and resultant contractile dysfunction.

PMID: 27955979 [PubMed - as supplied by publisher]

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