Affiliations: | | Weill Institute for Cell and Molecular Biology | Cornell University, Ithaca, NY, United States |
Area:
Dendrite morphogenesis
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High-probability grants
According to our matching algorithm, Chun Han is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2016 — 2020 |
Han, Chun |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of the Recognition of Degenerating Dendrites
Project Summary/Abstract Local degeneration of neuronal processes is an important mechanism in neural circuit remodeling and neuronal injury. The neuronal debris resulting from degeneration must be promptly cleared by phagocytes to prevent inflammation and to facilitate the subsequent neuronal regrowth. Although aberrant recognition and clearance of neuronal debris are implicated in neuroinflammation, autoimmunity, and neurodegenerative diseases, it is unknown how phagocytes distinguish degenerative neurites from surrounding healthy ones. In particular, three important questions remain unanswered: what is the signal on degenerating neurites that allows the recognition by phagocytes? What is the receptor for the recognition signal of degenerating neurites? How is the recognition signal specifically exposed on degenerating neurites? Our new in vivo data provided important clues that will help us to solve these puzzles. Using our new in vivo probes, we discovered that the ?eat-me? signal phosphatidylserine (PS) is absent on the surface of healthy dendrites but is exposed on degenerating dendrites in both developmental remodeling and physical injury. Building on these observations, this project aims to elucidate the in vivo mechanisms of PS exposure and recognition in dendrite degeneration using Drosophila sensory neurons as a model system. Our long term objective is to uncover autonomous and non-autonomous mechanisms of dendrite degeneration and repair. For this project, we propose the following three aims: 1) Determine the role of PS exposure in the recognition and engulfment of degenerating dendrites. The necessity of PS exposure in engulfment of dendrites after injury will be determined by (i) masking PS on the dendrite surface with PS-binding proteins, and (ii) blocking the biosynthesis of PS in specific neurons. The sufficiency of PS in triggering dendrite engulfment and degeneration will be tested by ectopically inducing PS exposure in neurons. 2) Investigate how the CED-1 family member Draper recognizes degenerating dendrites. Our results suggest that Draper recognizes degenerating dendrites. Two complementary in vivo competition assays will be performed to determine if Draper directly interacts with PS. 3) Determine how PS exposure is regulated in neurons and degenerating dendrites. By conducting loss-of-function studies of candidate genes, the identities of PS flippases and scramblases that regulate PS exposure during dendrite degeneration will be determined. The role of caspases in PS exposure will be investigated by examining caspase activity after dendrite injury and by disrupting the caspase pathway in neurons. Together, these aims will reveal in vivo mechanisms of neuronal debris sensing. As the clearance of neuronal debris in both mammals and insects requires the same CED-1 family of engulfment receptor, this study will reveal conserved mechanisms that may be relevant to neurodegenerative disorders.
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1 |
2017 — 2018 |
Han, Chun |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
A Light-Inducible Protein Trapping System For Studying Cellular Dynamics in Drosophila
PROJECT SUMMARY/ABSTRACT Spatiotemporal regulation of cellular dynamics is fundamental to animal development. A thorough understanding of developmental mechanisms requires approaches that permit in vivo perturbation of endogenous proteins in a spatially and temporally controlled manner. Such approaches are particularly important for understanding neuronal morphogenesis and the etiology of neurological disorders, as neurons usually occupy broad spatial domains and exhibit diverse growth dynamics at different dendritic and axonal branches. However, existing techniques for manipulating endogenous gene function in animal models, such as gene knockout, RNAi, and protein degradation, affect the whole cell and require time to take effect, and therefore lack the spatial and temporal resolution needed for dissecting dynamic growth behaviors of neurons at the subcellular level. We propose to develop an optogenetic system in Drosophila to enable rapid inhibition of endogenous proteins in precisely defined regions of cells. This will be achieved by light-inducible trapping of GFP-tagged endogenous proteins in large protein clusters. Such a strategy should be effective for inhibiting proteins whose functions require specific subcellular locations. Our system will be tested in sensory neurons and epidermal epithelial cells of Drosophila larvae, two cell types that are relevant to a broad range of human diseases. Several endogenously tagged proteins of diverse size, subcellular localization, and function will be first tested in a protein trapping assay. To validate the effectiveness of light-induced protein inhibition, the roles of Rab5 and Fry in dendrite morphogenesis of Drosophila sensory neurons will be investigated using GFP- tagged endogenous proteins. Rab5 and Fry are important for dendritic patterning. However, it is unknown whether they control dendritic growth by locally regulating dendritic dynamics or by globally modulating gene expression. By locally inhibiting Rab5 and Fry in individual dendritic branches, it will be determined whether they regulate local dendritic dynamics. The primary goal of this project is to establish the first Drosophila light- inducible loss-of-function system for investigating the local and moment-to-moment function of endogenous proteins in vivo. The increasing number of endogenous proteins tagged by GFP in Drosophila and the convenience of CRISPR/Cas9-mediated genome editing make our approach applicable to the study of a wide variety of proteins, biological processes, and human diseases. Our approach should also be applicable in other model organisms.
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