The goal of this Program Project Grant, entitled "Cell Autonomous and Non-autonomous Mechanisms of Aging" is to examine the mechanisms by which spontaneous, stochastic damage drives aging. This Program seeks to challenge the current notion that stochastic cellular damage, in particular, DNA damage promotes aging through a predominantly cell-autonomous mechanism by triggering programmed cell death or senescence. Although it is well-established that in response to high doses of genotoxic stress cells can secrete senescence-associated factors, which have a paracrine effect on neighboring cells, no one has established that non-cell autonomous events drive aging in response to physiological levels of endogenous DNA damage in vivo. The proposed experiments will address a model of aging where age-dependent accumulation of stochastic damage, including DNA damage, drives aging through both cell autonomous and non-autonomous pathways. This Program Project is comprised of three highly integrated projects. Project 1 (Laura Niedernhofer) will examine the cell autonomous and non-autonomous effects of DNA damage, measuring oxidative DNA damage, cellular senescence, ROS levels and aging-related pathology. Project 2 (Paul Robbins) will examine the cell autonomous and non-autonomous roles of NF-KB, a transcription factor activated in response to cellular damage and stress, in driving senescence, ROS and oxidative DNA damage with aging. Finally, Project 3 (Johnny Huard) will analyze the cell autonomous and non-autonomous pathways involved in age-related loss of stem cell function, as well as identify the factors secreted by functional adult stem cells that extend lifespan and healthspan. All projects will use tissues and cells from naturally aged mice and mouse models of accelerated aging, including mice in which ERCC1 is deleted tissue-specifically to affect the rate of DNA damage one tissue at a time. The projects will be supported by four cores, A) Administrative (Paul Robbins);B) Mouse Models (Laura Niedernhofer);C) Imaging (Simon Watkins) and D) Proteomics (Nathan Yates).
In order to develop therapeutic strategies for delaying onset of age-related pathology, a better understanding of the underlying cause(s) of aging is required. The goal of this Program Project Grant is to identify key mechanisms driving aging and age-related pathologies through both cell autonomous and non-autonomous mechanisms using mouse models of accelerated and natural aging.
|Kelley, Eric E; Baust, Jeff; Bonacci, Gustavo et al. (2014) Fatty acid nitroalkenes ameliorate glucose intolerance and pulmonary hypertension in high-fat diet-induced obesity. Cardiovasc Res 101:352-63|
|Robbins, Paul D; Morelli, Adrian E (2014) Regulation of immune responses by extracellular vesicles. Nat Rev Immunol 14:195-208|
|Fu, Lijuan; Guerrero, Candace R; Zhong, Na et al. (2014) Tet-mediated formation of 5-hydroxymethylcytosine in RNA. J Am Chem Soc 136:11582-5|
|Lu, Aiping; Poddar, Minakshi; Tang, Ying et al. (2014) Rapid depletion of muscle progenitor cells in dystrophic mdx/utrophin-/- mice. Hum Mol Genet 23:4786-800|
|Vaezi, Alec E; Bepler, Gerold; Bhagwat, Nikhil R et al. (2014) Choline phosphate cytidylyltransferase-? is a novel antigen detected by the anti-ERCC1 antibody 8F1 with biomarker value in patients with lung and head and neck squamous cell carcinomas. Cancer 120:1898-907|
|Takayama, Koji; Kawakami, Yohei; Lee, Sahnghoon et al. (2014) Involvement of ERCC1 in the pathogenesis of osteoarthritis through the modulation of apoptosis and cellular senescence. J Orthop Res 32:1326-32|
|Fox, Ira J; Daley, George Q; Goldman, Steven A et al. (2014) Stem cell therapy. Use of differentiated pluripotent stem cells as replacement therapy for treating disease. Science 345:1247391|