Research into the molecular, genetic, and cellular aspects of aging has greatly expanded our understanding of the basic processes that contribute to both longevity and age-related diseases. The primary focus of this Program since its inception is the assertion that age-dependent increases in oxidative stress and alterations in cellular Ca2+-handling converge to produce several of the well-known manifestations of aging, such as progressive muscle weakness and compromised cognitive performance. Our past efforts have led to the identification of protein markers of oxidative stress and the characterization of the effects of oxidation and aging on critical Ca -regulating proteins, using both in vivo and in vitro models of aging. We also made a number of important observations supporting the occurrence of oxidative modifications on proteins involved in Ca2+signaling in aging tissues. Over the past few years, enormous shifts have occurred in the overall research enterprise, primarily due to the sequencing of the human genome and development of new technologies for the analysis of transcriptional, translational, and signaling events occurring in cells and tissues. As a result, the strategies that Program participants are using to study the aging process have evolved to take advantage of the latest research advances. The major theme for the overall research effort, though, continues to be oxidative stress and Ca2+ regulation in aging. New approaches involving sub-proteomic studies of protein complexes, genomics, and transgenic mouse models of metabolic stress and recovery of structure and function, are now integral components of the research in this Program. The application is a resubmission for renewal of the Program Project and consists of 3 Projects: Project 1, Sarcopenia and Apoptosis: Role of SERCA and Bcl-2;Project 2, Age-Dependent Changes in Synaptic Raft Domains and Plasma Membrane Ca2+-ATPase;Project 3, Glutamate Neurotransmission, Aging, Longevity and Neurite Remodeling. The activities of the 2 scientific Cores have been expanded to provide new services and essential expertise needed to accomplish the aims of the projects. Core B was expanded to include detailed lipid analyses of neuronal membranes from aging tissues and protein isotopic labeling methods for quantification of protein changes. Electron microscopy and quantitative imaging were added to Core C. Core A, B and C were all expanded to include enhanced data sharing, relational databases, and bioinformatics analytical tools for systematic integration of the information from the Projects. The short term objectives for the Program are to define the molecular changes in neurons and muscle cells during aging that bring about altered control of intracellular Ca2+, metabolic stress, oxidative stress, initiation of apoptotic events, and cell recovery processes. The long-term objectives are to characterize the molecular events involved in the induction of two debilitating conditions of the aged, sarcopenia (muscle cell loss/ loss of muscle strength) and selective neurodegeneration. It is hoped that defining the molecular and cellular processes that produce these conditions of aging may lead to the discovery of new targets for future therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG012993-13
Application #
7796822
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2 (O1))
Program Officer
Wise, Bradley C
Project Start
1997-08-15
Project End
2013-02-28
Budget Start
2010-03-15
Budget End
2011-02-28
Support Year
13
Fiscal Year
2010
Total Cost
$2,000,136
Indirect Cost
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Hewarathna, Asha; Dremina, Elena; Schöneich, Christian (2017) Inhibition and conformational change of SERCA3b induced by Bcl-2. Biochim Biophys Acta 1865:121-131
Schöneich, Christian (2016) Thiyl radicals and induction of protein degradation. Free Radic Res 50:143-9
Poole, Leslie B; Schöneich, Christian (2015) Introduction: What we do and do not know regarding redox processes of thiols in signaling pathways. Free Radic Biol Med 80:145-7
Nauser, Thomas; Koppenol, Willem H; Schöneich, Christian (2015) Protein thiyl radical reactions and product formation: a kinetic simulation. Free Radic Biol Med 80:158-63
Badawi, Yomna; Pal, Ranu; Hui, Dongwei et al. (2015) Ischemic tolerance in an in vivo model of glutamate preconditioning. J Neurosci Res 93:623-32
Choi, In-Young; Lee, Phil; Wang, Wen-Tung et al. (2014) Metabolism changes during aging in the hippocampus and striatum of glud1 (glutamate dehydrogenase 1) transgenic mice. Neurochem Res 39:446-55
Wang, Xinkun; Patel, Nilam D; Hui, Dongwei et al. (2014) Gene expression patterns in the hippocampus during the development and aging of Glud1 (Glutamate Dehydrogenase 1) transgenic and wild type mice. BMC Neurosci 15:37
Schöneich, Christian; Dremina, Elena; Galeva, Nadezhda et al. (2014) Apoptosis in differentiating C2C12 muscle cells selectively targets Bcl-2-deficient myotubes. Apoptosis 19:42-57
Jiang, Lei; Bechtel, Misty D; Bean, Jennifer L et al. (2014) Effects of gangliosides on the activity of the plasma membrane Ca2+-ATPase. Biochim Biophys Acta 1838:1255-65
Wang, Shu-Lin; Sun, Liuchao; Fang, Jianwen (2014) Molecular cancer classification using a meta-sample-based regularized robust coding method. BMC Bioinformatics 15 Suppl 15:S2

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