Regulation of the Intestinal Stem Cell Niche in Aging

Summary

Principal Investigator: Omer Yilmaz
Abstract: DESCRIPTION (provided by applicant): A fundamental question in the aging field is whether the age-related decline in tissue-specific adult stem cell function is reversible. Focused on the gut, our preliminary studies suggest that intestinal stem cell (ISC) numbers are reduced in old mice and humans and that intestinal crypts isolated from old mice are less functional in an in vitro organoid assay of ISC function. We also find that calorie restriction (CR) reverses the effects of aging on ISCs. In the mammalian intestine, a majority of ISCs express Lgr5 and are adjacent to Paneth cells, which constitute a component of the stem cell cellular neighborhood or "niche". We have recently demonstrated that CR in young mice augments ISC function by reducing mechanistic target of rapamycin complex 1 (mTORC1) signaling in Paneth cells, and that these effects of CR can be mimicked by rapamycin (an mTORC1 inhibitor). This interaction between Paneth cells and ISCs is mediated by expression in Paneth cells of bone stromal antigen 1 (Bst-1), an ectoenzyme that produces the paracrine factor cyclic ADP ribose (cADPR). Identification of the mechanistic steps in this process through the three aims of this proposal wil increase our understanding of how CR protects an organism against the age-related decline in tissue function. Specifically, we will test the hypotheses that induction of niche Bst-1 by CR and rapamycin boosts ISC function in old mice (Aim 1);that the transcription factor PPAR-gamma mediates this response in Paneth cells (Aim 2);and that cADPR-activated signaling mediates this response in ISCs (Aim 3).
Funding Period: 2013-09-01 - 2015-05-31
more information: NIH RePORT

Top Publications

  1. pmc Dietary and metabolic control of stem cell function in physiology and cancer
    Maria M Mihaylova
    Whitehead Institute for Biomedical Research, Cambridge, MA 02142 USA Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, MA 02142, USA The David H Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA Department of Biology, MIT, Cambridge, MA 02139, USA
    Cell Stem Cell 14:292-305. 2014

Research Grants

Detail Information

Publications1

  1. pmc Dietary and metabolic control of stem cell function in physiology and cancer
    Maria M Mihaylova
    Whitehead Institute for Biomedical Research, Cambridge, MA 02142 USA Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, MA 02142, USA The David H Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA Department of Biology, MIT, Cambridge, MA 02139, USA
    Cell Stem Cell 14:292-305. 2014
    ..Here we will explore the emerging effects of diet on nutrient-sensing pathways active in mammalian tissue stem cells and their relevance to normal and cancerous growth. ..

Research Grants31

  1. Integrative Analysis of Longitudinal Studies of Aging
    Andrea M Piccinin; Fiscal Year: 2013
    ..abstract_text> ..
  2. Impact of Amyloid on the Aging Brain
    Reisa A Sperling; Fiscal Year: 2013
    ..This PPG brings together an exceptional multidisciplinary team of clinical, statistical, cognitive neuroscience, imaging, and laboratory investigators dedicated to exploring the impact of amyloid on the aging brain. ..
  3. Molecular Mechanisms of Blood Cell Transfusion
    LESLIE ERIC SILBERSTEIN; Fiscal Year: 2013
    ..Collectively, this program will yield significant insight and information that will directly translate into optimization of existing cell therapies and development of new ones. ..
  4. Eliciting B cells to produce anti-HIV gp41 MPER-specific neutralizing antibodies
    Ellis L Reinherz; Fiscal Year: 2013
    ..In conjunction with Projects 1- 3, kinetics of memory B cell and long-lived plasma cell populations will be ascertained and optimized. An Administrative Core with a Partnership Plan is included. ..
  5. Functional and molecular characteristics of Paneth cells during injury and repair
    Christopher M Dekaney; Fiscal Year: 2013
    ..The studies are innovative because they use a novel Paneth cell reporter model, novel stem cell culture models and extend upon new findings that Paneth cell expansion is an integral component of epithelial repair after injury. ..
  6. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
    ..This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship. ..
  7. Regulation of Active and Quiescent Intestinal Stem Cells
    Kelley Yan; Fiscal Year: 2013
    ..Achievement of these Aims should provide insight into the molecular differences between active and quiescent ISCs at the transcriptional level and their differential regulation by diverse pathways governing organ size and metabolism. ..
  8. STUDIES OF ORGAN TRANSPLANTATION IN ANIMALS AND MAN
    Arthur J Matas; Fiscal Year: 2013
    ..2. To maximize rehabilitation. The focus here is on minimizing complications and maximizing quality of life. ..
  9. Quantitative Systems Biology
    John D Aitchison; Fiscal Year: 2013
    ..In order to support this development, we form collaborations and transfer knowledge to the community, beginning with K-12 science education, and continuing through to professional development courses. ..
  10. Viral And host mechanisms that tilt the HSV lytic/latent balance
    Donald M Coen; Fiscal Year: 2013
    ..This research wil define basic mechanisms of herpes simplex virus latent infection and new targets for potential drugs to treat the latent infection of these viruses. ..
  11. Strategies for Improved Shock Wave Lithotripsy
    JAMES ALEXANDER MCATEER; Fiscal Year: 2013
    ..and the session can be ended * Determine the mechanism by which cavitation within a vessel causes hemorrhage * Develop numerical models to understand the role of cavitation and non-cavitational mechanisms in causing tissue damage ..
  12. Mitochondrial Dysfunction in Neurodegeneration of Aging
    Gary E Gibson; Fiscal Year: 2013
    ..Successful completion of the goals of these projects can be expected to provide new insights into neurodegenerative processes and contribute to novel approaches to ameliorating age-related neurodegenerations. ..
  13. Osteocyte Regulation of Bone/Muscle with Age
    Lynda F Bonewald; Fiscal Year: 2013
    ..The results of these experiments should lead to novel therapeutics for the prevention and treatment of both osteoporosis and sarcopenia. ..
  14. Restoring Mycocardial Healing
    MARK ALAN SUSSMAN; Fiscal Year: 2013
    ..The goal of this program will be to delineate these deleterious signaling mechanisms and determine how they can be overcome to restore endogenous cellular repair processes that heal the damaged heart. ..
  15. A novel colonic crypt base secretory cell that supports colon stem cells
    MICHAEL EVAN ROTHENBERG; Fiscal Year: 2013
    ..Preliminary data support the feasibility of all 3 aims. Ultimately, an improved understanding of the colon stem cell niche may enable development of novel targeted treatments for digestive diseases. ..
  16. Cell Growth Signaling in Cancer Development
    David M Sabatini; Fiscal Year: 2013
    ..Moreover, the signaling mechanisms we uncover may serve in the future as targets for the development of therapies that mimic some of the beneficial effects of CR. ..
  17. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..
  18. Cellular and molecular mechanisms of aging and regeneration in colonial chordate
    Irving L Weissman; Fiscal Year: 2013
    ..Thus the Botryllus model organism is a powerful tool to elucidate the role of stem cell aging on aging and regeneration processes. ..
  19. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  20. Novel Mechanistic Targets of Steroid Hormones in the Brain
    Meharvan Singh; Fiscal Year: 2013
    ....
  21. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  22. Mentoring Translational Cancer Research in Oklahoma
    Danny N Dhanasekaran; Fiscal Year: 2013
    ..3. To foster and enhance collaborations between basic scientists and clinicians, and to facilitate translational research directed toward the development of new diagnostics and treatments for cancer. ..
  23. Cadiorenal and Metabolic Diseases Research Center
    John E Hall; Fiscal Year: 2013
    ..abstract_text> ..
  24. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  25. Arterial Dysfunction: Basic and Clinical Mechanisms
    Thomas Michel; Fiscal Year: 2013
    ..Gladyshev. P. Libby directs the Redox Biomarkers Core;metabolic characterizations of mouse models studied in this Program will take place at the Yale Mouse Metabolic Phenotyping Center, led by G. Shulman. ..
  26. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..
  27. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
    ....
  28. Developmental Exposure Alcohol Research Center
    Linda Patia Spear; Fiscal Year: 2013
    ..Thus, the DEARC will serve as a nexus of alcohol research in Central New York and as a beacon for national activities. ..