1985 |
Orr, William C. |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Regulation of Chorion Gene Amplification |
0.957 |
1996 — 1999 |
Orr, William C. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Regulation of Antioxidative Genes and Aging @ Southern Methodist University |
0.931 |
1998 — 2010 |
Orr, William C. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Glutathione, Oxidative Stress, and Aging @ Southern Methodist University
[unreadable] DESCRIPTION (provided by applicant): The overarching goal of the proposed research is to directly test the validity of the oxidative stress hypothesis of aging by determining the effects of genetic manipulations of the antioxidative defenses in Drosophila melanogaster. The specific hypothesis to be tested in the present study is that experimental augmentation of the glutathione (GSH) - NADPH system would lower the level of oxidative stress thereby slowing the rate of the aging process, while a decrease in the efficiency of this system would elevate the level of oxidative stress and accelerate the aging process. GSH and NADPH provide the bulk of the reducing power in cells and act in concert to eliminate various reactive oxygen species (ROS). Enhancement of cellular ability to synthesize GSH and NADPH will be achieved by transgenic overexpression of y-glutamate-cysteine ligase subunits (GCL) and glucose-6-phosphate dehydrogenase (G6PH), respectively, in D. melanogaster. The four specific aims are: (I) Determine the effects of over and under expression of GCL in different regions of the body and at different periods of life cycle on the aging process. (II) Determine the effects of over and under expression of glucose-6-phosphate dehydrogenase (G6PD) in different regions of the body and at different periods of the life cycle on the aging process. (Ill) Determine the effects of co-overexpression of GCL and G6PD on the life span and patterns of physiological aging. (IV) Determine the effects of over and under expression of GCL and G6PD on the redox state of tissues indicated by GSH, GSSG, mixed protein disulfides, NADPH, NADP+, NADH and NAD+. The most compelling rationale for these studies is that our recent findings indicate that overexpression of GCL (catalytic subunit) and G6PD increases life span of relatively long-lived strains of flies by up to 50%. Results of the prospective studies would directly test the predictions of the oxidative stress hypothesis of aging and indicate whether augmentation of cellular reductive capacity can significantly extend the life span of flies. [unreadable] [unreadable]
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0.931 |
2002 — 2006 |
Orr, William C. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Thioredoxin Peroxidases, Oxidative Stress, and Aging @ Southern Methodist University
DESCRIPTION: (provided by applicant) The thioredoxin peroxidases represent a group of recently identified components of the antioxidative network, which reduce H2O2 and organic peroxides using thioredoxin as an electron source. These ubiquitous species are thought to play a particularly critical role in insects, given the lack of glutathione peroxidase activity in these animals. The purpose of the present study is to determine if the enhancement of thioredoxin peroxidase activity would lower the level of oxidative stress, thereby slowing the rate of the aging process, while a reduction in activity would increase the level of oxidative stress and accelerate the rate of aging. The specific focus of this study will be two distinct thioredoxin peroxidase genes, which are expressed at high levels in the adult tissues of Drosophila melanogaster. One of them has been localized to the mitochondria (DPx-5037), while the other has been identified as a secreted form (DPx-4 156). Reduction in thioredoxin peroxidase activity will be accomplished in Drosophila by under-expression, through RNA interference and/or the through the use of mutant alleles isolated by standard genetic approaches. Enhancement of thioredoxin peroxidase activity will be accomplished by over-expression by transgenic methodology, either using transgenes under control of the native promoters or engineered to be inducible by antibiotic administration. The effects of over- and under-expresssion of these genes on life span and a variety of biochemical/physiological alterations related to the aging process will be determined. Results should (i) provide a direct test of the role of the thioredoxin peroxidases in the aging process, (ii) permit further assessment of the validity of the oxidative stress hypothesis of aging, and (iii) aid in the design of similar studies in mammals.
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0.931 |
2017 |
Orr, William C. |
R15Activity Code Description: Supports small-scale research projects at educational institutions that provide baccalaureate or advanced degrees for a significant number of the Nation’s research scientists but that have not been major recipients of NIH support. The goals of the program are to (1) support meritorious research, (2) expose students to research, and (3) strengthen the research environment of the institution. Awards provide limited Direct Costs, plus applicable F&A costs, for periods not to exceed 36 months. This activity code uses multi-year funding authority; however, OER approval is NOT needed prior to an IC using this activity code. |
Peroxiredoxin 6 and Alzheimer's @ Southern Methodist University
A major pathological feature of Alzheimer's Disease (AD) is neuroinflammation, which has been characterized as both a cause and a consequence of chronic oxidative stress. Oxidative stress and inflammatory reactions are combatted by different antioxidant and redox-regulating factors. One such factor is the thiol-dependent peroxidase, Peroxiredoxin 6 (Prx6), which is known to possess antioxidant function through its peroxidase activity (PRX) and to regulate inflammation through its phospholipase activity (PLA). It is expressed at high levels in Alzheimer's patients and, when overexpressed in a mouse AD model, actually exacerbates the AD phenotype. We propose to use the Drosophila model to test the hypothesis that it is the phospholipase activity in the Prx6 gene that elicits a chronic state of inflammation and contributes to the Alzheimer's phenotype. In Drosophila, there exist two Prx6 variants, one of which (dPrx2540) is equivalent to the bifunctional mammalian form while the other (dPrx6005) does not possess PLA activity. The objectives of this proposal are two-fold. In Aim 1 both the bifunctional variant dPrx2540 as well as the variant possessing only peroxidase activity (dPrx6005) will be overexpressed in brain tissue to determine their relative impact in AD and control backgrounds, using a battery of tests, including survivorship, neuronal pathology and physical activity. In Aim 2, dPrx6 isoform transgenes will be engineered in which either the peroxidase activity or the phospholipase activity or both are ablated and these will be used to generate transgenic lines. We will then be in a position to determine the differential roles of PLA and PRX activities of the bifunctional dPrx2540 on AD progression. This will be achieved by transgene expression targeted specifically to neuronal tissue in both AD and normal backgrounds. A positive outcome in this endeavor would point to a series of potential targets for translational research, ranging from phospholipase activity to arachidonic acid and other downstream effectors of inflammation.
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0.927 |
2019 |
Orr, William C. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Foxp1 as a Therapeutic Target For Huntington's Disease @ Southern Methodist University
SUMMARY Huntington disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of a CAG repeat in the first exon of the huntingtin gene resulting in a mutant protein with a poly-glutamine expansion. Although mutant huntingtin (mut-Htt) is expressed ubiquitously in the brain, neurodegeneration occurs selectively in the striatum and, to a lesser degree, the cortex. We propose that a key factor in the region-specific vulnerability in HD is a reduction in the expression of FoxP1, a neuroprotective protein that is expressed selectively in medium spiny neurons of the striatum and to a relatively lower level in pyramidal neurons of the cortex. Consistent with our hypothesis, FoxP1 expression is reduced in the striatum of HD patients and HD mouse models. Elevating FoxP1 expression in cultured neurons protects them from mut-Htt toxicity, while knocking down its expression induces death in otherwise healthy neurons. The overall objective of the proposal is to understand the mechanism underlying the reduced expression of FoxP1 in dying neurons and the mechanism by which FoxP1 maintains the survival of neurons normally. Although almost all studies on FoxP1 have focused on a 90 kDa form of the protein called isoform-A, the brain expresses two other major isoforms ? isoforms C and D. The significance of these isoforms as well as other members of the FoxP family that are expressed in the adult striatum will be studied. Finally, we will extend our tissue culture studies to mice and examine whether elevated expression of FoxP1 protects mice from HD and whether the reduced striatal size in brain-specific FoxP1 conditional mice (cKO) is due to neuronal loss. The specific aims of this proposal are: Aim 1: Role of histone deacetylase-3 (HDAC3) and methyl CpG binding protein-2 (MeCP2) in the downregulation of FoxP1 expression in dying neurons. Aim 2: Aim 2: Identify downstream targets of FoxP1 that mediate its protective effect against mut-Htt neurotoxicity. Aim 3: To examine contribution of major FoxP1 isoforms and of FoxP2 and FoxP4 to neuronal survival. Aim 4: Examine the effects of modulating FoxP1 levels on the regulation of neurodegeneration and neuronal survival in vivo. There are currently no effective treatment strategies for the abnormal neuronal loss that occurs in HD. Successful completion of this project has the potential to provide new avenues for the development of a therapy to reduce or stop neurodegeneration in HD.
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0.931 |