Astrocytes play a key role in the protection and maintenance of the brain. Neuronal glutathione levels (GSH) are rapidly depleted during oxidative stress, and its re-synthesis is dependent on astrocyte GSH production. These physiological functions requires that astrocytes be capable of rapidly increasing their metabolic activity. During aging, little is known about the cumulative effects of oxidative damage on astrocytes. Degradation of their supportive and neuroprotective functions is likely to contribute to the aging process. Evidence is presented showing that astrocyte neuroprotection is diminished with age. It is also demonstrated that astrocyte resistance to oxidative stress and neuroprotection can be enhanced by activation of a purinergic receptor (P2Y-R) signaling pathway in cultured astrocytes as well as in whole animal models. This enhanced protection pathway appears to be dependent on increased mitochondrial function in astrocytes. The long-term goal of this proposal is to understand the role of astrocytes in the maintenance and protection of the brain during aging. The overall hypothesis is that neuroprotection can be enhanced by increasing mitochondrial metabolism in astrocytes at anytime during the aging process. The following Specific Aims are proposed to test this hypothesis. 1) To determine the mechanism by which purinergic receptor (P2Y-R) activation in astrocytes increases neuroprotection in the living mouse cortex throughout aging. 2) To define the impact of mitochondrial ROS damage on P2Y-R mediated astrocyte neuroprotection during the aging process in vivo. 3) To non-invasively delineate the receptor dependence of Ca2+ stimulated mitochondrial metabolism in astrocytes for in vivo neuroprotection during aging. Young, middle-aged and old mice as well from animal models with dysfunctional mitochondria and altered antioxidant enzyme activity will be used to carry out these aims. Single and mutliphoton microscopy will be used to image changes in mitochondrial and cellular function in vivo. Small animal fluorescent imaging will be used to monitor the progression of focal cerebral infarcts (strokes) in living mice brains. These studies are important to understand the underlying mechanisms of aging in humans. The identification and characterization of a novel protective pathway in the brain, which can be activated throughout the aging process, will also serve as an attractive therapeutic target to address many neuropathological processes.Accumulation of oxidative damage to astrocytes is likely to degrade their supportive and neuroprotective functions and significantly contribute to the aging process. Data collected from this research will help to identify and characterize novel protective pathways in astrocytes that can be activated to protect the brain during aging. These pathways should also serve as an attractive therapeutic targets to address many neuropathological processes, including stroke and dementias. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG029461-01A1
Application #
7373976
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Wise, Bradley C
Project Start
2008-03-15
Project End
2013-01-31
Budget Start
2008-03-15
Budget End
2009-01-31
Support Year
1
Fiscal Year
2008
Total Cost
$273,060
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Biology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Zheng, Wei; Talley Watts, Lora; Holstein, Deborah M et al. (2013) P2Y1R-initiated, IP3R-dependent stimulation of astrocyte mitochondrial metabolism reduces and partially reverses ischemic neuronal damage in mouse. J Cereb Blood Flow Metab 33:600-11
Diekman, Casey O; Fall, Christopher P; Lechleiter, James D et al. (2013) Modeling the neuroprotective role of enhanced astrocyte mitochondrial metabolism during stroke. Biophys J 104:1752-63
Paredes, R Madelaine; Bollo, Mariana; Holstein, Deborah et al. (2013) Luminal Ca2+ depletion during the unfolded protein response in Xenopus oocytes: cause and consequence. Cell Calcium 53:286-96
Chocron, E Sandra; Sayre, Naomi L; Holstein, Deborah et al. (2012) The trifunctional protein mediates thyroid hormone receptor-dependent stimulation of mitochondria metabolism. Mol Endocrinol 26:1117-28
Sayre, Naomi L; Lechleiter, James D (2012) Fatty acid metabolism and thyroid hormones. Curr Trends Endocinol 6:65-76
Zheng, Wei; Watts, Lora Talley; Holstein, Deborah M et al. (2010) Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria. PLoS One 5:e14401
Paredes, R Madelaine; Etzler, Julie C; Watts, Lora Talley et al. (2008) Chemical calcium indicators. Methods 46:143-51