2004 |
Cardozo-Pelaez, Fernando |
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. |
Aging of the Nigrostriatal System: Role of Dna Repair
[unreadable] DESCRIPTION (provided by applicant): The objective of this proposal is to define the role that age-dependent accumulation oxidative damage to DNA has in dictating the neuronal loss associated with aging. Specifically, this proposal aims to understand how an intrinsic factor, such as DNA repair capacity, has a major role in regulating DNA damage and how this interplay is crucial for the stability of specific neuronal populations during the normal process of aging. This information could be useful in gleaning on the mechanisms involved in neuropathologies associated with aging, such as Parkinson's disease. [unreadable] Specific Aim 1. To determine the status of DNA oxidation/DNA repair and stability of the nigrostriatal pathway of wild-type and mOggl knockout mice during aging. [unreadable] Specific Aim 2. To evaluate age-dependent effects in the antioxidant defenses of the nigrostriatal system and determine whether the lack of mOggl alters age-dependent changes in antioxidant systems. [unreadable] Specific Aim 3. To investigate whether lack of mOggl activity potentiates the loss of nigrostriatal DA neurons in murine MPTP-induced Parkinsonism. [unreadable] 129/SVJ male mice will used, the substantia nigra and caudate putamen of mice at ages 3, 12, 18, and 24 months will be analyzed for oxidative damage to DNA, DNA repair capacity, and integrity of the nigral-caudate putamen circuitry, as assessed by dopamine levels in caudate putamen and tyrosine hydroxylase neurons in substantia nigra. To determine, whether intact DNA repair is essential in maintaining normal neuronal populations during aging, similar studies will be carried out in mice lacking mOggl (glycosylase responsible for removal of oxo8dG). To identify the response that certain neuronal populations have in overcoming elevated oxidative stress, activities and levels of endogenous antioxidant system will be assessed at each age selected for the study. Wild type and knockout mice will be challenged with the neurotoxin MPTP in order to detect changes in the dopaminergic neurons susceptibility as a consequence of aging and lack of DNA repair [unreadable] [unreadable]
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2004 |
Cardozo-Pelaez, Fernando |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
Mechanisms of Dna Damage in Aging and Neurodegeneration
DNA damage; neural degeneration; pathologic process; aging;
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2005 |
Cardozo-Pelaez, Fernando |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
Mt Cobre: Mechanisms of Dna Damage in Aging and Neurodegeneration |
1 |
2006 — 2009 |
Cardozo-Pelaez, Fernando |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
Mt Cobre: Glutathione: Linking Dna Repair Regulation and Neuronal Vulnerability |
1 |
2009 — 2012 |
Cardozo-Pelaez, Fernando |
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. |
Oxidative Damage to Dna: Implications For Neurodegeneration in Aging
DESCRIPTION (provided by applicant): Oxidative damage to DNA: implications for neurodegeneration in aging Accumulation of the oxidatively damaged DNA base 8-hydroxy-2'-deoxyguanosine (oxo8dG) in distinct brain regions afflicted by neuronal loss is a common finding in aging and neurological disease. It has been shown that surviving neurons in brain regions impacted in age-related neurological deficits carry increased levels of oxo8dG;and recently it has been demonstrated that prior to neuronal degeneration there is a significant increase in oxo8dG levels in nuclear DNA. However, the mechanism of neuronal death triggered by elevated oxo8dG levels remains unknown. We have used a mice model that is deficient or null for the expression of the enzyme 8-hydroxyglycosylase, Ogg1, required for the repair of oxo8dG. These mice accumulate oxo8dG in an inverse relation to the level of Ogg1 expression and such an accumulation is accentuated by aging. Initial analyses show that lack of Ogg1 leads to an age-dependent loss in the nigrostriatal system and an increased susceptibility to dopaminergic toxins. In addition, we have found that Ogg1 expression appears to be dependent to changes in the redox state of the cell. Thus, we hypothesize that oxo8dG levels are not only epiphenomena of neurodegeneration, but a player in the neurodegenerative cascade. The studies in this proposal are aimed to establish a quantal relation between oxidative DNA damage and age-dependent and toxicological loss of the nigrostriatal system identifying the neurodegenerative mechanism involved (Specific Aim 1). Specific Aim 2 will discern the cellular triggers that control Ogg1 expression, which will allow us to glimpse mechanism that allow for accumulation of oxo8dG in neurons and alter cell vulnerability. Specific Aim 3 is designed to test the hypothesis that reestablishing Ogg1 expression in nigral dopaminergic neurons will afford neuroprotection. This model of increased susceptibility and accelerated age-dependent loss in the nigrostriatal system will allow us to test novel pharmacological and genetic manipulations to evaluate neuroprotective approaches, the simplicity of one gene one pathology can help us glean into direct mechanisms leading to neuronal loss and relevant therapeutic implications. PUBLIC HEALTH RELEVANCE: The development of most neurodegenerative diseases is associated with increased oxidative damage to DNA;however, the mechanisms associated with oxidative damage-driven neuronal loss in neurodegenerative diseases is poorly understood. This proposal is designed to address such mechanisms and to use this information to design therapeutic approaches that target oxidative damage to DNA aimed to treat or prevent disease.
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