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Principal Investigator: Jiajie Diao
Organization: UNIVERSITY OF CINCINNATI
Fiscal Year: 2024
Award: $405,000
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY
Autophagy is a crucial catabolic pathway by which cellular waste is recycled. Autophagic dysfunction has
been implicated in cellular quality control, responses to stress, development, lifespan, and a range of
infectious and other diseases in humans, including cancer, neurodegenerative diseases, and diabetes. The
crosstalk of organelles including fusion and contact is a critical process involved in autophagosome
biogenesis. The exact molecular mechanism for the crosstalk of organelles in autophagy remains far from
clear and thus a major topic of investigation. Since organelle crosstalk could act as a switch to spatially and
temporally regulate the autophagic flux in human diseases due to its dysregulation, dissecting and
controlling the regulatory machinery is essential to understanding the exact roles of autophagy in specific
disease contexts. Therefore, studying the molecular mechanism of organelle crosstalk will provide the
opportunity to develop new therapeutic strategies in order to control activity of autophagy. We have
developed in vitro protein reconstitution systems and live cell super-resolution imaging assays to study the
dynamics and interactions of organelles. In this R35 renewal application, based on our preliminary data, we
hypothesize that the crosstalk of organelles including fusion and contact regulates autophagosome
biogenesis, in which SNAREs, vacuolar protein sorting-associated protein 33A (VPS33A), and Atg9 play a
critical role. In the next five years, we will 1) study v- and t- SNAREs and accessory proteins involved in
autophagosome maturation; 2) elucidate the role of Atg9 vesicle contact resulting in clustering for early
autophagosome biogenesis; 3) analyze and control the crosstalk between Atg9 vesicles and other
organelles. Systematical studies on the role of organelle fusion and contact in autophagosome biogenesis
through multiple biochemical, biophysical, and cell biological approaches are critical to elucidate detailed
molecular mechanisms, which could offer therapeutic advances. Moreover, an attempt to control organelle
dynamics and interactions by optogenetic tools would be an important expansion, which is also essential for
future drug development.
Terms: <Assay><Autophagocytosis><Autophagosome><Bioassay><Biochemical><Biogenesis><Biological><Biological Assay><Biophysics><Cancers><Cell Body><Cells><Data><Degenerative Neurologic Disorders><Development><Diabetes Mellitus><Disease><Disorder><Dysfunction><Functional disorder><Future><Human><In Vitro><Investigation><Malignant Neoplasms><Malignant Tumor><Modern Man><Molecular><NSF attachment protein receptor><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Organelles><Origin of Life><Pathway interactions><Physiopathology><Play><Process><Proteins><Quality Control><Recycling><Role><SNAP receptor><SNARE><Stress><System><Therapeutic><Vacuolar Protein Sorting><Vesicle><autophagy><biologic><biophysical foundation><biophysical principles><biophysical sciences><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><developmental><diabetes><drug development><human disease><life span><lifespan><malignancy><neoplasm/cancer><neurodegenerative illness><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><optogenetics><pathophysiology><pathway><protein reconstitution><response><social role><soluble N-ethylmaleimide-sensitive-factor attachment protein receptor><superresolution imaging><t-SNARE><target SNARE proteins><target membrane SNARE proteins><tool><wasting>