Project Details
Description
PROJECT SUMMARY
The long term goal of this project is to understand the regulation and physiological roles of autophagy, a
process by which proteins, organelles and bulk cytoplasm are sequestered within autophagic vesicles and
delivered to the lysosome for degradation. This process plays several distinct, vital roles in the cell, acting to
recycle aged or damaged components, to provide a source of nutrients in response to starvation, and in some
cases to initiate cell death. These cellular functions underlie a growing appreciation for the impact of autophagy
on a broad range of human illnesses and on normal physiological processes such as aging. Fundamental
questions regarding autophagy remain to be addressed, including how autophagy initiation is regulated by
nutrients and other signals, how autophagic vesicles mature to become competent for degradation, and how
rates of autophagy are maintained at homeostatic levels optimal for cell survival. The exciting prospect of
harnessing autophagy as a therapeutic tool awaits better understanding of these basic principals.
The proposed studies will use genetic, biochemical and imaging-based approaches in the Drosophila system
to help define mechanisms of autophagy regulation in the context of in an intact organism. Our previous
studies identified a number of key targets and mechanisms through which the Target of Rapamycin (TOR)
pathway inhibits autophagy in response to favorable nutrient conditions. The current proposal seeks to
understand 1) how TOR signaling is integrated with other nutrient and developmental cues such as cAMP-
dependent protein kinase A to control the initial steps of autophagy induction; 2) to test hypotheses that
describe potential mechanisms by which TOR signaling controls the fusion of autophagosomes with lysosomes
and the subsequent acidification of the autolysosome; and 3) to decipher the feedback mechanisms that
provide homeostatic control limiting the rates and levels of autophagic activity.
Experiments in this proposal were selected for their likelihood of having a high impact on key questions
important to the field of autophagy. This proposal makes use of recently developed reagents including
knockouts of several autophagy-related (Atg) genes, in vivo markers of autophagic activity, and novel methods
of genetic manipulation in cell clones. Information gained from studies of autophagy in Drosophila will provide
an important whole-animal complement to mammalian cell culture-based studies.
Status | Active |
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Effective start/end date | 8/1/21 → 5/31/24 |
Funding
- National Institute of General Medical Sciences: $328,687.00
- National Institute of General Medical Sciences: $328,687.00
- National Institute of General Medical Sciences: $328,687.00
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