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Search Results: 1 - 10 of 402649 matches for " Margaret M DeAngelis "
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Modifier Genes as Therapeutics: The Nuclear Hormone Receptor Rev Erb Alpha (Nr1d1) Rescues Nr2e3 Associated Retinal Disease
Nelly M. Cruz, Yang Yuan, Barrett D. Leehy, Rinku Baid, Uday Kompella, Margaret M. DeAngelis, Pascal Escher, Neena B. Haider
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0087942
Abstract: Nuclear hormone receptors play a major role in many important biological processes. Most nuclear hormone receptors are ubiquitously expressed and regulate processes such as metabolism, circadian function, and development. They function in these processes to maintain homeostasis through modulation of transcriptional gene networks. In this study we evaluate the effectiveness of a nuclear hormone receptor gene to modulate retinal degeneration and restore the integrity of the retina. Currently, there are no effective treatment options for retinal degenerative diseases leading to progressive and irreversible blindness. In this study we demonstrate that the nuclear hormone receptor gene Nr1d1 (Rev-Erbα) rescues Nr2e3-associated retinal degeneration in the rd7 mouse, which lacks a functional Nr2e3 gene. Mutations in human NR2E3 are associated with several retinal degenerations including enhanced S cone syndrome and retinitis pigmentosa. The rd7 mouse, lacking Nr2e3, exhibits an increase in S cones and slow, progressive retinal degeneration. A traditional genetic mapping approach previously identified candidate modifier loci. Here, we demonstrate that in vivo delivery of the candidate modifier gene, Nr1d1 rescues Nr2e3 associated retinal degeneration. We observed clinical, histological, functional, and molecular restoration of the rd7 retina. Furthermore, we demonstrate that the mechanism of rescue at the molecular and functional level is through the re-regulation of key genes within the Nr2e3-directed transcriptional network. Together, these findings reveal the potency of nuclear receptors as modulators of disease and specifically of NR1D1 as a novel therapeutic for retinal degenerations.
Identifying subtypes of patients with neovascular age-related macular degeneration by genotypic and cardiovascular risk characteristics
Michael Feehan, John Hartman, Richard Durante, Margaux A Morrison, Joan W Miller, Ivana K Kim, Margaret M DeAngelis
BMC Medical Genetics , 2011, DOI: 10.1186/1471-2350-12-83
Abstract: We identified a sample of patients with neovascular AMD, that in previous studies had been shown to be at elevated risk for the disease through environmental factors such as cigarette smoking and genetic variants including the complement factor H gene (CFH) on chromosome 1q25 and variants in the ARMS2/HtrA serine peptidase 1 (HTRA1) gene(s) on chromosome 10q26. We conducted a multivariate segmentation analysis of 253 of these patients utilizing available epidemiologic and genetic data.In a multivariate model, cigarette smoking failed to differentiate subtypes of patients. However, four meaningfully distinct clusters of patients were identified that were most strongly differentiated by their cardiovascular health status (histories of hypercholesterolemia and hypertension), and the alleles of ARMS2/HTRA1 rs1049331.These results have significant personalized medicine implications for drug developers attempting to determine the effective size of the treatable neovascular AMD population. Patient subtypes or clusters may represent different targets for therapeutic development based on genetic pathways in AMD and cardiovascular pathology, and treatments developed that may elevate CV risk, may be ill advised for certain of the clusters identified.The current medical literature is increasing weekly with studies identifying DNA variants and their possible interaction with environmental factors that may have impact on risk of disease. The growth of such studies has been spurred by the promise of understanding the genetic and environmental basis of complex diseases, and the possibility of identifying therapeutically responsive targets for drug development. Enormous numbers of DNA variants have been associated with diseases and traits and this number will only grow as it becomes economically feasible to sequence an individual patient's entire genome[1].One key data interpretation challenge lies in how best to assess the phenotypic heterogeneity and risk factor heterogeneity with
Germline BAP1 Inactivation Is Preferentially Associated with Metastatic Ocular Melanoma and Cutaneous-Ocular Melanoma Families
Ching-Ni Jenny Njauw, Ivana Kim, Adriano Piris, Michele Gabree, Michael Taylor, Anne Marie Lane, Margaret M. DeAngelis, Evangelos Gragoudas, Lyn M. Duncan, Hensin Tsao
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0035295
Abstract: Background BAP1 has been shown to be a target of both somatic alteration in high-risk ocular melanomas (OM) and germline inactivation in a few individuals from cancer-prone families. These findings suggest that constitutional BAP1 changes may predispose individuals to metastatic OM and that familial permeation of deleterious alleles could delineate a new cancer syndrome. Design To characterize BAP1's contribution to melanoma risk, we sequenced BAP1 in a set of 100 patients with OM, including 50 metastatic OM cases and 50 matched non-metastatic OM controls, and 200 individuals with cutaneous melanoma (CM) including 7 CM patients from CM-OM families and 193 CM patients from CM-non-OM kindreds. Results Germline BAP1 mutations were detected in 4/50 patients with metastatic OM and 0/50 cases of non-metastatic OM (8% vs. 0%, p = 0.059). Since 2/4 of the BAP1 carriers reported a family history of CM, we analyzed 200 additional hereditary CM patients and found mutations in 2/7 CM probands from CM-OM families and 1/193 probands from CM-non-OM kindreds (29% vs. 0.52%, p = .003). Germline mutations co-segregated with both CM and OM phenotypes and were associated with the presence of unique nevoid melanomas and highly atypical nevoid melanoma-like melanocytic proliferations (NEMMPs). Interestingly, 7/14 germline variants identified to date reside in C-terminus suggesting that the BRCA1 binding domain is important in cancer predisposition. Conclusion Germline BAP1 mutations are associated with a more aggressive OM phenotype and a recurrent phenotypic complex of cutaneous/ocular melanoma, atypical melanocytic proliferations and other internal neoplasms (ie. COMMON syndrome), which could be a useful clinical marker for constitutive BAP1 inactivation.
The NEI/NCBI dbGAP database: Genotypes and haplotypes that may specifically predispose to risk of neovascular age-related macular degeneration
Hong Zhang, Margaux A Morrison, Andy DeWan, Scott Adams, Michael Andreoli, Nancy Huynh, Maureen Regan, Alison Brown, Joan W Miller, Ivana K Kim, Josephine Hoh, Margaret M DeAngelis
BMC Medical Genetics , 2008, DOI: 10.1186/1471-2350-9-51
Abstract: Before release of individual data, p-value information was obtained directly from the AREDS dbGAP website. Of the 35 variants with P < 10-6 examined, 23 significantly modified risk of neovascular AMD. Many variants located in tandem on 1q32-q22 including those in CFH, CFHR4, CFHR2, CFHR5, F13B, ASPM and ZBTB were significantly associated with AMD risk. Of these variants, single SNP analysis revealed that CFH rs572515 was the most significantly associated with AMD risk (P < 10-6). Haplotype analysis supported our findings of single SNP association, demonstrating that the most significant haplotype, GATAGTTCTC, spanning CFH, CFHR4, and CFHR2 was associated with the greatest risk of developing neovascular AMD (P < 10-6). Other than variants on 1q32-q22, only two SNPs, rs9288410 (MAP2) on 2q34-q35 and rs2014307 (PLEKHA1/HTRA1) on 10q26 were significantly associated with AMD status (P = .03 and P < 10-6 respectively). After controlling for smoking history, gender and age, the most significant gene-gene interaction appears to be between rs10801575 (CFH) and rs2014307 (PLEKHA1/HTRA1) (P < 10-11). The best genotypic fit for rs10801575 and rs2014307 was an additive model based on LRT. After applying a Bonferonni correction, no other significant interactions were identified between any other SNPs.This is the first replication study on the NEI dbGAP SNPs, demonstrating that alleles on 1q, 2q and 10q may predispose an individual to AMD.Advanced age-related macular degeneration (AMD) is the most common cause of legal blindness in developed countries. Clinically two forms of advanced AMD are recognized: geographic atrophy and neovascular. Geographic atrophy is characterized by a slow progressive degeneration of the retinal pigment epithelium (RPE), resulting in the gradual loss of the photoreceptors. The neovascular form is characterized by the growth of new abnormal blood vessels from beneath the retina that can cause severe and rapid vision loss due to hemorrhage and exudation.
Clinical validation of a genetic model to estimate the risk of developing choroidal neovascular age-related macular degeneration
Gregory S Hageman, Karen Gehrs, Serguei Lejnine, Aruna T Bansal, Margaret M DeAngelis, Robyn H Guymer, Paul N Baird, Rando Allikmets, Cosmin Deciu, Paul Oeth, Lorah T Perlee
Human Genomics , 2011, DOI: 10.1186/1479-7364-5-5-420
Abstract: Many diseases of ageing characterised by complex inheritance patterns are progressive; the individual may be asymptomatic in the early stages. One of these diseases, age-related macular degeneration (AMD), is the most common cause of visual impairment and the leading cause of blindness in the elderly population in the developed world. The prevalence of AMD increases with advancing age in all populations studied. Thus, in developed nations such as the USA, UK, Canada and Australia, with increasingly aged populations, the condition affects a progressively larger segment of the population and has become a major public health issue. Early- or late-stage AMD is present in 15 per cent of individuals over the age of 60 years [1]. It is estimated that there are currently 9.1 million patients in the USA with AMD, of which 1.7 million suffer with the vision-threatening late-stage complications of choroidal neovascularisation (CNV) or geographic atrophy [1]. Moreover, it is predicted that the number of cases of early AMD will increase to 17.8 million by 2050 and, if untreated, cases of late-stage blinding AMD will increase to 3.8 million [1]. It has been determined that vision loss from AMD decreases quality of life by 60 per cent, similar to the experience of dealing with a stroke that requires intensive nursing care [2].The clinical presentation and natural course of AMD are highly variable. The disease may present as early as the fifth decade of life or as late as the ninth decade. The clinical symptoms of AMD range from no visual disturbances in early disease to profound loss of central vision in the advanced late stages of the disease. Some patients never progress beyond early AMD; however, in 10-15 per cent of Caucasian patients with early-stage disease, the condition progresses to an exudative neovascular (or 'wet' form) or geographic atrophic (or 'dry' form) AMD, which threatens vision. The phenotype is characterised by development of subretinal choroidal neovascular c
Genetic Variations Strongly Influence Phenotypic Outcome in the Mouse Retina
Austin S. Jelcick, Yang Yuan, Barrett D. Leehy, Lakeisha C. Cox, Alexandra C. Silveira, Fang Qiu, Sarah Schenk, Andrew J. Sachs, Margaux A. Morrison, Arne M. Nystuen, Margaret M. DeAngelis, Neena B. Haider
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021858
Abstract: Variation in genetic background can significantly influence the phenotypic outcome of both disease and non-disease associated traits. Additionally, differences in temporal and strain specific gene expression can also contribute to phenotypes in the mammalian retina. This is the first report of microarray based cross-strain analysis of gene expression in the retina investigating genetic background effects. Microarray analyses were performed on retinas from the following mouse strains: C57BL6/J, AKR/J, CAST/EiJ, and NOD.NON-H2-nb1 at embryonic day 18.5 (E18.5) and postnatal day 30.5 (P30.5). Over 3000 differentially expressed genes were identified between strains and developmental stages. Differential gene expression was confirmed by qRT-PCR, Western blot, and immunohistochemistry. Three major gene networks were identified that function to regulate retinal or photoreceptor development, visual perception, cellular transport, and signal transduction. Many of the genes in these networks are implicated in retinal diseases such as bradyopsia, night-blindness, and cone-rod dystrophy. Our analysis revealed strain specific variations in cone photoreceptor cell patterning and retinal function. This study highlights the substantial impact of genetic background on both development and function of the retina and the level of gene expression differences tolerated for normal retinal function. These strain specific genetic variations may also be present in other tissues. In addition, this study will provide valuable insight for the development of more accurate models for human retinal diseases.
DNA sequence variants in the LOXL1 gene are associated with pseudoexfoliation glaucoma in a U.S. clinic-based population with broad ethnic diversity
Bao Fan, Louis Pasquale, Cynthia L Grosskreutz, Douglas Rhee, Teresa Chen, Margaret M DeAngelis, Ivana Kim, Elizabeth del Bono, Joan W Miller, Tiansen Li, Jonathan L Haines, Janey L Wiggs
BMC Medical Genetics , 2008, DOI: 10.1186/1471-2350-9-5
Abstract: Three LOXL1 SNPs were genotyped in a patient sample (206 pseudoexfoliation, 331 primary open angle glaucoma, and 88 controls) from the Glaucoma Consultation Service at the Massachusetts Eye and Ear Infirmary. The SNPs were evaluation for association with pseudeoexfoliation syndrome, pseudoexfoliation glaucoma, and primary open angle glaucoma.The strongest association was found for the G allele of marker rs3825942 (G153D) with a frequency of 99% in pseudoexfoliation patients (with and without glaucoma) compared with 79% in controls (p = 1.6 × 10-15; OR = 20.93, 95%CI: 8.06, 54.39). The homozygous GG genotype is also associated with pseudoexfoliation when compared to controls (p = 1.2 × 10-12; OR = 23.57, 95%CI: 7.95, 69.85). None of the SNPs were significantly associated with primary open angle glaucoma.The pseudoexfoliation syndrome is a common cause of glaucoma. These results indicate that the G153D LOXL1 variant is significantly associated with an increased risk of pseudoexfoliation and pseudoexfoliation glaucoma in an ethnically diverse patient population from the Northeastern United States. Given the high prevalence of pseudooexfoliation in this geographic region, these results also indicate that the G153D LOXL1 variant is a significant risk factor for adult-onset glaucoma in this clinic based population.Glaucoma is one of the leading causes of blindness worldwide and results in an irreversible degeneration of the optic nerve that is usually associated with a high intraocular pressure. The disease is clinically and genetically heterogeneous with early onset forms exhibiting mendelian inheritance while the common late onset forms have a more complex genetic architecture. Several genes have been associated with the mendelian forms of early-onset glaucoma: defects in the myocilin gene (GLC1A) primarily cause elevated pressure [1,2], the optineurin gene (GLC1E), appears to contribute to disease in familial low tension glaucoma [3-5]; and the WDR36 gene (GLC1G) may b
Up Against The Wall: The Effects of Climate Warming on Soil Microbial Diversity and The Potential for Feedbacks to The Carbon Cycle
Grace Pold,Kristen M. DeAngelis
Diversity , 2013, DOI: 10.3390/d5020409
Abstract: Earth’s climate is warming, and there is evidence that increased temperature alters soil C cycling, which may result in a self-reinforcing (positive), microbial mediated feedback to the climate system. Though soil microbes are major drivers of soil C cycling, we lack an understanding of how temperature affects SOM decomposition. Numerous studies have explored, to differing degrees, the extent to which climate change may affect biodiversity. While there is ample evidence that community diversity begets ecosystem stability and resilience, we know of keystone species that perform functions whose effects far outweigh their relative abundance. In this paper, we first review the meaning of microbial diversity and how it relates to ecosystem function, then conduct a literature review of field-based climate warming studies that have made some measure of microbial diversity. Finally, we explore how measures of diversity may yield a larger, more complete picture of climate warming effects on microbial communities, and how this may translate to altered carbon cycling and greenhouse gas emissions. While warming effects seem to be ecosystem-specific, the lack of observable consistency between measures is due in some part to the diversity in measures of microbial diversity.
Molecular Interactions in the Development of Brain Metastases
Nina Martinez,Adrienne Boire,Lisa M. DeAngelis
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms140817157
Abstract: Brain metastases are a much-feared complication of cancer. The development of brain metastases requires a malignant cell to acquire characteristics that facilitate dissemination away from the primary site, entrance into the nervous system, and establishment in the brain. This review summarizes recent work focused on the molecular derangements leading to brain metastases and outlines areas in need of greater understanding.
Influence of ROBO1 and RORA on Risk of Age-Related Macular Degeneration Reveals Genetically Distinct Phenotypes in Disease Pathophysiology
Gyungah Jun, Michael Nicolaou, Margaux A. Morrison, Jacqueline Buros, Denise J. Morgan, Monte J. Radeke, Yoshihiro Yonekawa, Evangelia E. Tsironi, Maria G. Kotoula, Fani Zacharaki, Nissa Mollema, Yang Yuan, Joan W. Miller, Neena B. Haider, Gregory S. Hageman, Ivana K. Kim, Debra A. Schaumberg, Lindsay A. Farrer, Margaret M. DeAngelis
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025775
Abstract: ROBO1 is a strong candidate gene for age-related macular degeneration (AMD) based upon its location under a linkage peak on chromosome 3p12, its expression pattern, and its purported function in a pathway that includes RORA, a gene previously associated with risk for neovascular AMD. Previously, we observed that expression of ROBO1 and RORA is down-regulated among wet AMD cases, as compared to their unaffected siblings. Thus, we hypothesized that contribution of association signals in ROBO1, and interaction between these two genes may be important for both wet and dry AMD. We evaluated association of 19 single nucleotide polymorphisms (SNPs) in ROBO1 with wet and dry stages of AMD in a sibling cohort and a Greek case-control cohort containing 491 wet AMD cases, 174 dry AMD cases and 411 controls. Association signals and interaction results were replicated in an independent prospective cohort (1070 controls, 164 wet AMD cases, 293 dry AMD cases). The most significantly associated ROBO1 SNPs were rs1387665 under an additive model (meta P = 0.028) for wet AMD and rs9309833 under a recessive model (meta P = 6×10?4) for dry AMD. Further analyses revealed interaction between ROBO1 rs9309833 and RORA rs8034864 for both wet and dry AMD (interaction P<0.05). These studies were further supported by whole transcriptome expression profile studies from 66 human donor eyes and chromatin immunoprecipitation assays from mouse retinas. These findings suggest that distinct ROBO1 variants may influence the risk of wet and dry AMD, and the effects of ROBO1 on AMD risk may be modulated by RORA variants.
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