The overall goal of this grant application is to determine the mitochondrial mechanism and relative neuroprotective potency of a panel of non-feminizing estrogen-like, estratrienes, using a structure-activity relationship (SAR) approach. These compounds are selected from novel compounds synthesized in our Drug Synthesis Core as well as more than 60 estratrienes discovered during the previous funding period to be potent neuroprotectants, but to lack interaction with either ERalpha or ERbeta. The estratrienes will include compounds more potent and compounds less potent than 17 beta-E2. This goal will be achieved by addressing 5 specific aims.
Specific Aim will determine the SAR of neuroprotection and mitochondrial membrane potential (delta-psi) in two cell types in vitro.
Specific Aim 2 will determine the SAR of neuroprotection and Ca 2+ increase in cytosol and mitochondria of two cell types in vitro.
Specific Aim 3 will determine the SAR of neuroprotection and blockade of activation of cyclin dependent kinases in an in vivo model for cerebral ischemia-reperfusion.
Specific Aim 4 will determine the SAR of neuroprotection and tau hyperphosphorylation in an in vivo model for cerebral ischemia-reperfusion. Transient middle cerebral artery (MCA) occlusion will be used to activate tau hyperphosphorylation and the potency of estratrienes in neuroprotection and blockade of tau hyperphosphorylation will be determined. Finally, Specific Aim 5 will determine the SAR of neuroprotection and tau hyperphosphorylation/ neurofibrillary tangle (NFTs) in an in vivo model using local cortical transduction of human mutated tau (p301L) and cerebral ischemia-reperfusion. Collectively, achieving these specific aims requires coordination with the Vector Core (Core B), the Neuroimaging Core (Core C), and the Drug Synthesis Core (Core D) and will substantially advance our understanding of the potential for clinical development of estratrienes for the prevention/treatment of Alzheimer's disease. The need for this research program is critical, given the recent WHI reports of prothrombic and carcinogenic toxicities of PremPro(R) in elderly women. There is a critical need for the discovery of potent, non-feminizing estrogens in the management of post-menopausal hormone-deprivation syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG010485-18
Application #
7796641
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
18
Fiscal Year
2009
Total Cost
$249,524
Indirect Cost
Name
University of North Texas
Department
Type
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
Richter, Frank; Koulen, Peter; Kaja, Simon (2016) N-Palmitoylethanolamine Prevents the Run-down of Amplitudes in Cortical Spreading Depression Possibly Implicating Proinflammatory Cytokine Release. Sci Rep 6:23481
Means, John C; Gerdes, Bryan C; Kaja, Simon et al. (2016) Caspase-3-Dependent Proteolytic Cleavage of Tau Causes Neurofibrillary Tangles and Results in Cognitive Impairment During Normal Aging. Neurochem Res 41:2278-88
Montgomery, Christa L; Keereetaweep, Jantana; Johnson, Heather M et al. (2016) Changes in Retinal N-Acylethanolamines and their Oxylipin Derivatives During the Development of Visual Impairment in a Mouse Model for Glaucoma. Lipids 51:857-66
Kaja, Simon; Payne, Andrew J; Singh, Tulsi et al. (2015) An optimized lactate dehydrogenase release assay for screening of drug candidates in neuroscience. J Pharmacol Toxicol Methods 73:1-6
Sarkar, Saumyendra; Jun, Sujung; Simpkins, James W (2015) Estrogen amelioration of A?-induced defects in mitochondria is mediated by mitochondrial signaling pathway involving ER?, AKAP and Drp1. Brain Res 1616:101-11
Kaja, Simon; Payne, Andrew J; Naumchuk, Yuliya et al. (2015) Plate reader-based cell viability assays for glioprotection using primary rat optic nerve head astrocytes. Exp Eye Res 138:159-66
Cheli, V T; Santiago González, D A; Spreuer, V et al. (2015) Voltage-gated Ca2+ entry promotes oligodendrocyte progenitor cell maturation and myelination in vitro. Exp Neurol 265:69-83
Kaja, Simon; Sumien, Nathalie; Shah, Vidhi V et al. (2015) Loss of Spatial Memory, Learning, and Motor Function During Normal Aging Is Accompanied by Changes in Brain Presenilin 1 and 2 Expression Levels. Mol Neurobiol 52:545-54
Kaja, S; Payne, A J; Nielsen, E Ø et al. (2015) Differential cerebellar GABAA receptor expression in mice with mutations in CaV2.1 (P/Q-type) calcium channels. Neuroscience 304:198-208
Grillo, Stephanie L; Koulen, Peter (2015) Psychophysical testing in rodent models of glaucomatous optic neuropathy. Exp Eye Res 141:154-63

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