The senescence of tissue stem cells, including that of hematopoietic stem cells (HSC), is a major underlying mechanism for aging of an organism. Despite extensive analysis, the underlying cause for senescence of HSC remains largely unresolved. Although it is generally accepted that both cell intrinsic and environmental factors are involved in senescence of tissue stem cells, how the environmental factor in the aging organisms translates into senescence of their HSC is unclear. The mTOR pathway has emerged as a major sensor for environmental and nutrient conditions of many cell types. In the past several years, my laboratory has been investigating the role of mTOR in the function of HSC. Our preliminary data demonstrated that the mTOR pathway is over-activated in the aging HSC and that such activation is both necessary and sufficient to cause functional defects of HSC, as well as HSC senescence. The underlying cause of mTOR activation remained unknown. Here we plan to take biochemical, genetic and immunological approaches to identify the cause of mTOR activation in aging HSC. As part of our effect to demonstrate essential role for mTOR activation in HSC aging, we showed that a six-week treatment with rapamycin can rejuvenate the aging HSC. This result raised an intriguing potential to translate our fundamental discovery to clinical care of the increasingly older population. Our proposed studies are detailed in two specific aims.
Specific Aim I. To identify the root cause of enhanced inflammatory cytokine production and HSC senescence in the old mice.
Specific Aim II. To identify a potential therapeutic window for transient use of low dose rapamycin to rejuvenate aging HSC. This application is based on our several lines of exciting and innovative studies in TSC-mTOR pathway in HSC function and in HSC senescence, as well as a novel pathway in regulating immune response to cell injury published in J. Exp. Med., Science Signaling and Science in past two years. Our proposed studies will not only elucidate a fundamental mechanism of HSC aging, but also provide novel approaches for therapeutic rejuvenation of HSC. The completion of the proposed study will have both immediate and long term impact for clinical application.

Public Health Relevance

Aging of hematopoietic stem cells (HSC) is a major underlying mechanism for aging, affecting the immune system and increased leukemia incidence. The mTOR pathway has emerged as a major sensor for environmental and nutrient conditions of many cell types. Since the aging organism exhibits higher levels of inflammatory cytokines, and since some of the inflammatory cytokines have been shown to activate mTOR pathway, we have formulated a central hypothesis: Inflammatory cytokine produced in the aging organism triggers HSC senescence by activation of mTOR pathway. We will examine: (1). What is the molecular mechanism of elevated inflammatory cytokine production and HSC senescence in the old mice? (2) Is there a therapeutic window for short-term use of rapamycin to rejuvenate aging HSC? Our proposed studies have the potential to demonstrate inflammation as the underlying cause of HSC senescence. This will not only elucidate a fundamental mechanism of HSC aging, but also provide novel approaches for therapeutic rejuvenation of HSC. The study will have both immediate and long term impact in clinical application.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG036690-02
Application #
8149834
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Fuldner, Rebecca A
Project Start
2010-09-30
Project End
2015-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$306,407
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Tang, Fei; Zhang, Peng; Ye, Peiying et al. (2017) A population of innate myelolymphoblastoid effector cell expanded by inactivation of mTOR complex 1 in mice. Elife 6:
Tanno, Toshihiko; Zhang, Peng; Lazarski, Christopher A et al. (2017) An aptamer-based targeted delivery of miR-26a protects mice against chemotherapy toxicity while suppressing tumor growth. Blood Adv 1:1107-1119
Ichiyama, Kenji; Gonzalez-Martin, Alicia; Kim, Byung-Seok et al. (2016) The MicroRNA-183-96-182 Cluster Promotes T Helper 17 Cell Pathogenicity by Negatively Regulating Transcription Factor Foxo1 Expression. Immunity 44:1284-98
Liu, Yan; Wang, Yin; Du, Zhanwen et al. (2016) Fbxo30 Regulates Mammopoiesis by Targeting the Bipolar Mitotic Kinesin Eg5. Cell Rep 15:1111-1122
Wong, Chunshu; Chen, Chong; Wu, Qi et al. (2015) A critical role for the regulated wnt-myc pathway in naive T cell survival. J Immunol 194:158-67
Ye, Peiying; Liu, Yu; Chen, Chong et al. (2015) An mTORC1-Mdm2-Drosha axis for miRNA biogenesis in response to glucose- and amino acid-deprivation. Mol Cell 57:708-20
Wang, Lizhong; Liu, Runhua; Ye, Peiying et al. (2015) Intracellular CD24 disrupts the ARF-NPM interaction and enables mutational and viral oncogene-mediated p53 inactivation. Nat Commun 6:5909
Ichiyama, Kenji; Chen, Tingting; Wang, Xiaohu et al. (2015) The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells. Immunity 42:613-26
Chen, Guo-Yun; Brown, Nicholas K; Zheng, Pan et al. (2014) Siglec-G/10 in self-nonself discrimination of innate and adaptive immunity. Glycobiology 24:800-6
Thaxton, Jessica E; Liu, Bei; Zheng, Pan et al. (2014) Deletion of CD24 impairs development of heat shock protein gp96-driven autoimmune disease through expansion of myeloid-derived suppressor cells. J Immunol 192:5679-86

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