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["Title"," Principal Investigator"," Institution"," Grant Number"," RFA PA Number"," Program Officer"," Pubs"," Primary Science Code"," Secondary Science Code"," Abstract"]
["AUTONOMOUS MONITOR FOR TOXIC GAS EXPOSURE","Michalek, John ","Zebra Analytix, Inc.","R44ES032369","PA22-176","Ravichandran, Lingamanaidu",0,"74 - Biosensors/Biomarkers","03 - Carcinogenesis/Cell Transformation","Project Summary\n The overall goal of this SBIR project is to develop a miniature, microfabricated gas\nchromatography (micro GC) device for autonomous, near real-time monitoring of toxic VOCs\n(volatile organic compounds) in the workplace. A key differentiator is exploring a low-cost\nmultilayer fabrication process to develop a new-type micro GC. Through the Phase I project, a\nworking prototype of the proposed micro GC has been created and has demonstrated rapid and\nsensitive measurement of representative toxic VOCs in air. This Phase II study will further\noptimize the designs and fabrication of key micro GC components developed in Phase I and\ncreate a commercial prototype. Micro GC method development and validation for additional toxic\nVOCs, as well as pilot testing, will also be pursued in Phase II. The final product will be a plug-\nand-play toxic VOC monitor with online sampling and onboard calibration capabilities.\n Toxic or even carcinogenic VOCs can be emitted into the workplace and environment from\nmany industrial and chemical processes, posing a serious health hazard to workers as well as\nthe general public. Therefore, there is a critical need for sensitive and accurate monitoring of VOC\nexposure in real time or near real time. Unfortunately, existing approaches are associated with\nmajor limitations due to the lack of specificity (e.g., colorimetric detection tubes and\nphotoionization sensors), or because of the requirement of a bulky/expensive instrument or offline\nsampling (e.g., traditional GC methods). The proposed micro GC aims to overcome these\ndrawbacks and address the critical needed for autonomous, continuous, and specific monitoring\nof VOC exposure."]
["MOLECULAR ARCHITECTURE OF OXIDATIVE STRESS INDUCED DOUBLE STRAND BREAK REPAIR","Jamsen, Joonas ","Univ Of Arkansas For Med Scis","R00ES029572","PA16-193","Heacock, Michelle",0,"09 - Genome Integrity"," - ","Abstract\nExcess reactive oxygen and nitrogen species (RONS) from radiation, polluted air, as well as chemicals in food\nand water induce oxidative stress and cause direct damage to nucleotide bases. A prominent form of oxidized\ndamage in the genome and free nucleotide pools is 8-oxoG or 8-oxo-dGTP, respectively. 8-oxoG can hydrogen\nbond with adenine, resulting in mutations upon DNA replication. 8-oxoG also produces double strand breaks\n(DSBs) that undergo error-prone repair through non-homologous end-joining (NHEJ). This results in\nmutagenesis and genomic instability.\n DNA polymerases mediate repair of oxidative DNA damage. A major obstacle to understanding the\netiology and progression of diseases caused by oxidative stress is that the DNA polymerase mechanism\nemployed in the repair of oxidative lesions and effects of accessory factors in the DNA repair complex remain\npoorly understood. Solving this problem will enable a more complete understanding of the role of DNA\npolymerases in cancer, aging and disease. The knowledge gained will enable development of therapies to target\ncancer, neurodegenerative disorders and aging.\n I will uncover the impact of oxidative stress-induced DNA repair on genome integrity by determining how\nactive site contacts and dynamics in polymerases influence repair outcomes. I will also relate my observations\nto accessory repair factors and larger repair complexes. To accomplish this task, I will use pH jump\ncrystallography to determine snapshots that will reveal the active site contacts and dynamics employed by NHEJ\npolymerases λ and μ to insert and extend from an 8-oxoG lesion (Aim 1, K99 phase). The functional significance\nof these contacts will be verified using kinetic assays and mutant enzymes. I hypothesize that these contacts\nregulate the unique behavior of these polymerases in promoting productive and accurate synthesis and provide\ninsight into the role of 8-oxoG in mutagenesis. I will then employ a combination of transient kinetics and time-\nlapse crystallography to determine the atomic level contacts and dynamics employed by polymerases λ and μ\nto perform translesion synthesis past and proofreading of the 8-oxoG lesion (Aim 2, R00 phase). The structural\nintermediates determined in this aim will allow understanding of the structural requirements for mutation prone\nbypass of 8-oxoG. Building on the results of the latter two aims and training during the K99 period, I will determine\nthe role of substrate channeling among accessory factors during oxidative DNA damage induced NHEJ (Aim 3,\nR00 phase). Cryo-EM studies will enable determination of how the dynamic and heterogenous populations of\nNHEJ repair complexes impact oxidative DNA damage repair. I will also determine the structural basis for 8-\noxoG processing by Artemis during oxidative NHEJ repair. Completion of this aim will require training in Cryo-\nEM that will be provided by Dr. Mario Borgnia.\n The knowledge gained as a result of the work on how polymerases impact repair of oxidative damage\nand how this mediates productive repair will provide a significant advance in the understanding of how\nenvironmental agent induced DNA damage repair. I will gain expertise in state-of-the-art methods such as\ncrystallography, transient kinetics, cryo-EM, DNA replication and DNA repair that will help me achieve my career\ngoals and establish an independent laboratory."]
["RNA MODIFICATIONS BY PATERNAL EXPOSURE TO ARSENIC AND INTERGENERATIONAL EFFECTS ON SPERM QUALITY","Ho, Shuk-Mei ","Univ Of Arkansas For Med Scis","R01ES032675","PA20-185","Tyson, Frederick",0,"10 - Epigenetics","03 - Carcinogenesis/Cell Transformation","PROJECT SUMMARY\nInorganic arsenic (iAs) produces significant reproductive toxicity in adult males leading to decreased sperm\nquality. Aside from workplace exposure, individuals are exposed to high levels of iAs near hazardous waste sites\nand in geographic areas enriched with iAs. A recent study revealed that transient prenatal exposure to a high\ndose of iAs impaired sperm quality in multiple generations. However, it is not known whether paternal exposures\nto environmentally relevant dose of iAs during adolescence or early-life (gestation to weaning) produce adverse\ninheritable reproductive outcomes. We posit that adolescence and early-life are windows of susceptibility during\nwhich exposure to iAs negatively impacts not only the individuals being exposed but also their offspring. However,\nthe molecular mechanisms mediating paternal intergenerational transmission of exposure-induced traits remain\nunclear. Recently, sperm-borne small-RNAs and their specific 5'-methylcytosine (m5C) modifications were shown\nto mediate the paternal transmission of diet-induced disorders. Yet, similar studies on environmental toxicants such\nas iAs are absent. In our pilot study, we discovered iAs-induced changes in pseudouridine (Ψ) and m5C abundance\nin sperm small-RNAs. Ψ and m5C were found to be the most abundant RNA modifications in sperm small-RNAs,\nand we hypothesize that these modifications mediate the paternal inheritance of poor sperm quality associated\nwith iAs exposure, particularly during the developmental windows of adolescence (Aim 1) and early life (gestation\nto weaning) (Aim 2). We will determine if adolescent (Aim 1A) and early-life (Aim 2A) iAs exposure are windows\nof susceptibility conferring the intergenerational inheritance of impaired sperm quality. We will identify the\nmediating role of sperm small-RNAs and their modifications, Ψ and m5C, in adolescent (Aim 1B) and early-life\n(Aim 2B) exposure-induced paternal inheritance of impaired sperm quality by performing zygotic microinjection\n(ZI) of sperm small-RNA isolated from exposed or control mice to generate offspring from naïve zygotes. We\nexpect the offspring of the adolescent exposure group to have poorer sperm quality, as in exposed fathers and\nsons produced by natural mating. To validate the functional role of specific modifications in our sperm phenotype\ninheritance model, we will isolate Ψ- and m5C-enriched sperm small-RNA fractions by RNA immunoprecipitation\nfor zygotic microinjection. We will determine if microinjection of specific modification-enriched sperm small-RNAs\nduring adolescent (Aim 1C) and early-life (Aim 2C) can reproduce the paternal sperm phenotype. We expect the\nZI-produced offspring exposed to Ψ- or m5C-enriched sperm small-RNAs from adolescent and/or early-life\nexposure groups can recapitulate the poor sperm quality phenotypes. We will use Nanopore native RNAseq to\nmap sperm Ψ and m5C modifications and identify small-RNA populations associated with the exposure window-\nspecific intergenerational inheritance. Finally, we will correlate RNA epitranscriptomic and transcriptomic\nchanges with the intergenerational effects of adolescent/early-life iAs exposure on sperm quality."]

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