Endosomal compartments have diverse functions. In addition to their classic role in delivering internalized cargo to lysosomes for nutritional purposes and for the down- regulation of cell surface receptors, they also serve to direct biosynthetic cargo to a diverse set of lysosome-related organelles. The regulation of endocytic trafficking is also closely linked to autophagy which constitutes a second delivery pathway to lysosomes. This pathway accomplishes the engulfment of intracellular components into autophagosomes which ultimately fuse with lysosomes to degrade their content. Autophagy may be the most important defense cells have against the accumulation of damaged and aggregated proteins and dysfunctional organelles. Interference with autophagy hastens degenerative processes in the eye or other tissues and has also been linked to cancer. Drosophila constitutes an excellent model system to analyze a novel pathway that links the regulation of autophagy to that of endocytic trafficking. The dAcinus protein modulates endocytic trafficking and enhances signaling by the EGF and Notch receptors. dAcinus is also necessary for the normal maturation of autophagosomes whereas increased levels of dAcinus induce autophagy.
Aim 1 proposes to use genetic and transgenic approaches to determine which extracellular signals are responsible for the different aspects of the dynamic regulation of dAcinus in the developing eye.
Aim 2 will analyze which elements within the dAcinus protein mediate its regulation in the context of endocytic trafficking and autophagy.
Aim 3 will determine which targets in endocytic trafficking and autophagy are regulated by dAcinus function using a combination of next generation sequencing and genetic approaches.

Public Health Relevance

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Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010199-18
Application #
8403026
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
1994-04-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
18
Fiscal Year
2013
Total Cost
$302,100
Indirect Cost
$112,100
Name
University of Texas Sw Medical Center Dallas
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Kramer, Helmut (2013) Route to destruction: autophagosomes SNARE lysosomes. J Cell Biol 201:495-7
Maldonado-Báez, Lymarie; Cole, Nelson B; Krämer, Helmut et al. (2013) Microtubule-dependent endosomal sorting of clathrin-independent cargo by Hook1. J Cell Biol 201:233-47

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