The long term goal of this project is to understand the cellular and molecular mechanisms by which the Target of Rapamycin (TOR) kinase controls cell growth and metabolism. Work in the current budget period has established TOR as a central regulator of growth in Drosophila, and has characterized the upstream circuitry and downstream cellular processes that regulate and mediate TOR function. 1 critical unresolved question concerns the relative degree to which each of the cellular processes regulated by TOR contributes to its effects. The objective of the proposed work is to achieve a detailed understanding of how 1 such process, autophagy, contributes to TOR-dependent functions. Autophagy is a non-selective degradative process in which portions of cytoplasm are engulfed and sequestered into membrane-bound vesicles, and transported to the lysosome for breakdown and recycling. As the major route by which long-lived proteins, organelles and bulk cytoplasm are degraded, autophagy has a catabolic effect on cell growth and metabolism, and its breakdown products are essential for survival under conditions of starvation. Many of the genes that regulate autophagy have now been identified in yeast, and homologs of these genes have recently been shown to function in autophagy in metazoans. Work in our laboratory and others have shown that TOR signaling is necessary and sufficient to suppress autophagy under normal conditions;this function of TOR is conserved from yeast to human cells. We have developed a series of novel genetic reagents to induce, block or monitor autophagy in Drosophila. Using these reagents we propose to elucidate the role and regulation of autophagy in response to TOR signaling. The proposed work has 4 aims: 1) investigation of the contributions of autophagy to TOR-dependent growth, proliferation and survival;2) analysis of potential mechanisms by which autophagy influences cell growth;3) analysis of mechanisms by which TOR regulates autophagy;4) screen for novel genes required for autophagy in response to TOR signaling. TOR signaling has broad impacts on health-related issues such as tumorigenesis, neurodegeneration, and aging. Correlative and genetic data from a number of systems suggest autophagy contributes to these effects. By helping to reveal the molecular basis of TOR,Aos effects on cell growth and metabolism, this work will advance our basic understanding of these processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062509-09
Application #
7645711
Study Section
Cellular Signaling and Dynamics Study Section (CSD)
Program Officer
Zatz, Marion M
Project Start
2001-03-01
Project End
2010-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
9
Fiscal Year
2009
Total Cost
$279,050
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Genetics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Ayala, Carlos I; Kim, Jung; Neufeld, Thomas P (2018) Rab6 promotes insulin receptor and cathepsin trafficking to regulate autophagy induction and activity in Drosophila. J Cell Sci 131:
Kim, Jung; Bilder, David; Neufeld, Thomas P (2018) Mechanical stress regulates insulin sensitivity through integrin-dependent control of insulin receptor localization. Genes Dev 32:156-164
Neisch, Amanda L; Neufeld, Thomas P; Hays, Thomas S (2017) A STRIPAK complex mediates axonal transport of autophagosomes and dense core vesicles through PP2A regulation. J Cell Biol 216:441-461
Mauvezin, Caroline; Neisch, Amanda L; Ayala, Carlos I et al. (2016) Coordination of autophagosome-lysosome fusion and transport by a Klp98A-Rab14 complex in Drosophila. J Cell Sci 129:971-82
Braden, Christopher R; Neufeld, Thomas P (2016) Atg1-independent induction of autophagy by the Drosophila Ulk3 homolog, ADUK. FEBS J 283:3889-3897
Kim, Jung; Neufeld, Thomas P (2015) Dietary sugar promotes systemic TOR activation in Drosophila through AKH-dependent selective secretion of Dilp3. Nat Commun 6:6846
Mauvezin, Caroline; Nagy, Péter; Juhász, Gábor et al. (2015) Autophagosome-lysosome fusion is independent of V-ATPase-mediated acidification. Nat Commun 6:7007
Mauvezin, Caroline; Ayala, Carlos; Braden, Christopher R et al. (2014) Assays to monitor autophagy in Drosophila. Methods 68:134-9
Neufeld, Thomas P (2012) Autophagy and cell growth--the yin and yang of nutrient responses. J Cell Sci 125:2359-68
Jimenez-Sanchez, Maria; Menzies, Fiona M; Chang, Yu-Yun et al. (2012) The Hedgehog signalling pathway regulates autophagy. Nat Commun 3:1200

Showing the most recent 10 out of 35 publications