The mTOR pathway is a signaling system that regulates growth and metabolism in response to the nutritional state of the organism. Increasing evidence indicates that the pathway is commonly deregulated in cancer, neurodegeneration, and diabetes, and also plays a major role in the aging process. The large mTOR protein kinase is the target of the drug rapamycin and the catalytic subunit of two multi-protein complexes, mTOR Complex 1 (mTORC1) and 2 (mTORC2) that nucleate distinct branches of the mTOR pathway and respond to different upstream signals. mTORC1 responds to a diverse set of stimuli, such as growth factors, nutrients, and stresses, and regulates many anabolic and catabolic processes, including protein and lipid synthesis and autophagy. Recently, we discovered that mTORC1 regulates, in a non-cell autonomous fashion, the self-renewal of intestinal stem cells (ISCs) in response to caloric restriction (CR). mTORC1 acts in Paneth cells, which constitute the niche for ISCs and are located at the base of intestinal crypts. CR is a reduction in caloric restriction in the absence of malnutrition and has very interesting effects in mice, such as decreasing tumor growth and increasing lifespan. The mechanisms through which CR functions are not well understood in mammals. The broad goals of our work are to arrive at a mechanistic understanding of how mTORC1 senses the CR state in Paneth cells, how its activity modulates Paneth cell function to regulate ISCs, and to determine the implications of our work for understanding the effects of CR on tumorigenesis.
The specific aims of our proposed work are to: identify the mTORC1-dependent effectors through which CR acts in Paneth cells to promote ISC self renewal (Aim 1);determine the factors Paneth cells use to modulate intestinal ISC renewal in response to CR (Aim 2);and determine how CR and mTORC1 activity in Paneth cells regulate intestinal tumorigenesis (Aim 3). We will accomplish our goals with a multi- disciplinary approach that uses the tools of biochemistry, molecular biology, and mouse engineering. Our results are likely to have important consequences for our understanding of the clinically important mTOR pathway. 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.

Public Health Relevance

Growth is the fundamental process through which cells and organisms accumulate mass and increase in size. It has become increasingly apparent that the pathways that regulate growth become deregulated in common human diseases, such as cancer, diabetes, and degeneration. We have been studying in mammalian systems a network within cells called the 'mTOR pathway'that is a major growth regulator. A branch of this pathway called the 'mTORC1 pathway'senses the nutritional state of the organism to regulate many physiological processes. We have found that mTORC1 is a key regulator of the response of the mouse intestine to a dietary manipulation called caloric restriction or CR, in which the totl caloric intake is reduced without leading to malnutrition. CR has interesting effects in many organisms, including reducing cancer and increasing lifespan in mice. Our overarching goal is to increase our molecular understanding of the mTOR pathway and its physiological roles, so as to enable the medical community to exploit the pathway for therapeutic benefit. Our work should also help clarify the mechanisms through which CR acts in mammals.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA129105-06
Application #
8434396
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Spalholz, Barbara A
Project Start
2007-07-01
Project End
2018-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
6
Fiscal Year
2013
Total Cost
$402,576
Indirect Cost
$196,127
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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