National Institute of Environmental Health and Safety
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INC Research, Emory University, National Institute of Environmental Health, Safety, Veterans Affairs Puget Sound Health Care System and University of Oregon | Date: 2012-10-19

The present invention relates to methods of treatment for Parkinson Disease (PD) in a person by identifying gene variants which may indicate a more favorable response to specific medicaments, thereby allowing for personalized or individualized treatment. The present invention relates to a method of screening for a genetic predisposition to PD in a person. The present invention is also directed to a method of testing a person for the presence of particular gene variants, wherein the presence of a gene variant indicates a higher predisposition to PD, and the absence of a gene variant indicates a lower predisposition to PD, compared to a control sample. The present invention further relates to methods and kits for treating, or inhibiting the development of, PD in a person. The present invention is also directed to a method of identifying the heritage of an individual based on the genetic profile of the individual.

Birnbaum L.S.,National Health Research Institute | Jung P.,National Institute of Environmental Health and Safety
Health Affairs | Year: 2011

Environmental health science is the study of the impact of the environment on human health. This paper introduces basic topics in environmental health, including clean air, clean water, and healthful food, as well as a range of current issues and controversies in environmental health. Conceptual shifts in modern toxicology have changed the field. There is a new understanding of the effects of exposure to chemicals at low doses, and in combination, and the impact on human growth and development. Other emerging topics include the role of epigenetics, or changes in genes and gene expression that can be brought about by chemical exposure; environmental justice; and potential effects of engineered nanomaterials and climate change. We review the important implications for public health policy and recommend a broad environmental health research strategy aimed at protecting and improving human health. © 2011 Project HOPE-The People-to-People Health Foundation, Inc.

Wilcox A.J.,National Institute of Environmental Health and Safety | Weinberg C.R.,National Institute of Environmental Health and Safety | Basso O.,McGill University
American Journal of Epidemiology | Year: 2011

Preterm delivery is a powerful predictor of newborn morbidity and mortality. Such problems are due to not only immaturity but also the pathologic factors (such as infection) that cause early delivery. The understanding of these underlying pathologic factors is incomplete at best. To the extent that unmeasured pathologies triggering preterm delivery also directly harm the fetus, they will confound the association of early delivery with neonatal outcomes. This, in turn, complicates studies of newborn outcomes more generally. When investigators analyze the association of risk factors with neonatal outcomes, adjustment for gestational age as a mediating variable will lead to bias. In the language of directed acyclic graphs, gestational age is a collider. The theoretical basis for colliders has been well described, and gestational age has recently been acknowledged as a possible collider. However, the impact of this problem, as well as its implications for perinatal research, has not been fully appreciated. The authors discuss the evidence for confounding and present simulations to explore how much bias is produced by adjustments for gestational age when estimating direct effects. Under plausible conditions, frank reversal of exposure-outcome associations can occur. When the purpose is causal inference, there are few settings in which adjustment for gestational age can be justified. © 2011 The Author.

Copeland W.C.,National Institute of Environmental Health and Safety
Sub-cellular biochemistry | Year: 2010

Since mutations in mitochondrial DNA (mtDNA) have been shown to be a cause of many mitochondrial diseases as well as aging, it is important to understand the origin of these mutations and how replication proteins modulate this process. DNA polymerase gamma (pol gamma) is the polymerase that is responsible for replication and repair of mtDNA. Pol gamma has three main roles in mtDNA maintenance and mutagenesis. As the only known DNA polymerase in mitochondria, pol gamma is required for all replication and repair functions and is the main source of errors produced in human mtDNA. Pol gamma is also sensitive to a host of antiviral nucleoside analogs used to treat HIV-1 infections, which can cause an induced mitochondrial toxicity. Finally, the gene for pol gamma, POLG, is a genetic locus for several mitochondrial disease with over 150 genetic mutations currently identified.

Copeland W.C.,National Institute of Environmental Health and Safety
Critical Reviews in Biochemistry and Molecular Biology | Year: 2012

Mitochondrial DNA (mtDNA) is replicated by the DNA polymerase g in concert with accessory proteins such as the mtDNA helicase, single stranded DNA binding protein, topoisomerase, and initiating factors. Nucleotide precursors for mtDNA replication arise from the mitochondrial salvage pathway originating from transport of nucleosides, or alternatively from cytoplasmic reduction of ribonucleotides. Defects in mtDNA replication or nucleotide metabolism can cause mitochondrial genetic diseases due to mtDNA deletions, point mutations, or depletion which ultimately cause loss of oxidative phosphorylation. These genetic diseases include mtDNA depletion syndromes such as Alpers or early infantile hepatocerebral syndromes, and mtDNA deletion disorders, such as progressive external ophthalmoplegia (PEO), ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). This review focuses on our current knowledge of genetic defects of mtDNA replication (POLG, POLG2, C10orf2) and nucleotide metabolism (TYMP, TK2, DGOUK, and RRM2B) that cause instability of mtDNA and mitochondrial disease. © 2012 Informa Healthcare USA, Inc.

Roberts S.A.,National Institute of Environmental Health and Safety | Gordenin D.A.,National Institute of Environmental Health and Safety
BioEssays | Year: 2014

The gain of a selective advantage in cancer as well as the establishment of complex traits during evolution require multiple genetic alterations, but how these mutations accumulate over time is currently unclear. There is increasing evidence that a mutator phenotype perpetuates the development of many human cancers. While in some cases the increased mutation rate is the result of a genetic disruption of DNA repair and replication or environmental exposures, other evidence suggests that endogenous DNA damage induced by AID/APOBEC cytidine deaminases can result in transient localized hypermutation generating simultaneous, closely spaced (i.e. "clustered") multiple mutations. Here, we discuss mechanisms that lead to mutation cluster formation, the biological consequences of their formation in cancer and evidence suggesting that APOBEC mutagenesis can also occur genome-wide. This raises the possibility that dysregulation of these enzymes may enable rapid malignant transformation by increasing mutation rates without the loss of fitness associated with permanent mutators. © 2014 WILEY Periodicals, Inc.

Schellenberg M.J.,National Institute of Environmental Health and Safety | Appel C.D.,National Institute of Environmental Health and Safety | Adhikari S.,Georgetown University | Robertson P.D.,National Institute of Environmental Health and Safety | And 2 more authors.
Nature Structural and Molecular Biology | Year: 2012

The topoisomerase II (topo II) DNA incision-and-ligation cycle can be poisoned (for example following treatment with cancer chemotherapeutics) to generate cytotoxic DNA double-strand breaks (DSBs) with topo II covalently conjugated to DNA. Tyrosyl-DNA phosphodiesterase 2 (Tdp2) protects genomic integrity by reversing 5′-phosphotyrosyl-linked topo II-DNA adducts. Here, X-ray structures of mouse Tdp2-DNA complexes reveal that Tdp2 β-2-helix-β DNA damage-binding 'grasp', helical 'cap' and DNA lesion-binding elements fuse to form an elongated protein-DNA conjugate substrate-interaction groove. The Tdp2 DNA-binding surface is highly tailored for engagement of 5′-adducted single-stranded DNA ends and restricts nonspecific endonucleolytic or exonucleolytic processing. Structural, mutational and functional analyses support a single-metal ion catalytic mechanism for the exonuclease-endonuclease-phosphatase (EEP) nuclease superfamily and establish a molecular framework for targeted small-molecule blockade of Tdp2-mediated resistance to anticancer topoisomerase drugs. © 2012 Nature America, Inc. All rights reserved.

Rider L.G.,National Institute of Environmental Health and Safety | Miller F.W.,National Institute of Environmental Health and Safety
JAMA - Journal of the American Medical Association | Year: 2011

The idiopathic inflammatory myopathies or myositis syndromes (the most common forms are polymyositis, dermatomyositis, and inclusion body myositis) are systemic autoimmune diseases defined by chronic muscle weakness and inflammation of unknown etiology and result in significant morbidity and mortality. Research suggests that categorizing heterogeneous myositis syndromes into mutually exclusive and stable phenotypes by using clinical and immune response features is useful for predicting clinical signs and symptoms, associated genetic and environmental risk factors, and responses to therapy and prognosis. Knowledge of myositis phenotypes should enhance clinicians' ability to recognize and manage these rare disorders. ©2011 American Medical Association. All rights reserved.

Agency: NSF | Branch: Contract Interagency Agreement | Program: | Phase: | Award Amount: 86.85K | Year: 2011


Agency: NSF | Branch: Contract Interagency Agreement | Program: | Phase: | Award Amount: 335.59K | Year: 2011


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