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Common Regulatory Pathways for the Genesis of Lysosome-Related Organelles and Dynamics of Microtubules during Development

溶酶体相关细胞器的起源和发育过程中微管动力学的常见调控途径

基本信息

批准号：
10684931
负责人：
David M Glover
金额：
$ 43.79万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684931
关键词：
Affect Antigen-Presenting Cells Behavior Biogenesis Biological Blastoderm Blood Platelets CHS1 gene Cell Nucleus Cells Centrosome Co-Immunoprecipitations Coma Complex Cytoplasm Cytoplasmic Granules Cytotoxic T-Lymphocytes Defect Development Dissociation Dominant-Negative Mutation Drosophila genus Dynein ATPase Embryo Enabling Factors Endosomes Failure Female Film Genes Genetic Human Immunologics Immunoprecipitation In Vitro Knowledge Lysosomes Lytic Mass Spectrum Analysis Mediating Melanosomes Microtubule-Associated Proteins Microtubules Mitosis Modeling Molecular Mothers Mutate Mutation Oocytes Organelles Pathway interactions Patients Pharmaceutical Preparations Phenotype Pilot Projects Polyploidy Positioning Attribute Process Proteins Regulatory Pathway Reporting Research Resolution Role SNAP receptor System Testing Translating Vesicle cell type chediak-higashi syndrome dynactin gamma Tubulin gene product immunological synapse lysosomal proteins mutant protein transport recruit therapeutic development trafficking

项目摘要

PROJECT SUMMARY Lysosome-Related Organelles (LROs) contain both lysosomal proteins and cell-type specific proteins in an acidic lumen. They are enlarged in Chediak-Higashi Syndrome (CHS) patients resulting from either excessive fusion or inhibition of their fission. The mutated gene in CHS encodes the lysosomal trafficking regulator (LYST) protein, whose function is poorly understood. Defects in microtubule behavior and centrosome behavior are seen at the immunological synapse of CHS patients but whether microtubule nucleation is affected directly in CHS cells is controversial. To determine LYST's function in LROs and clarify its requirements at microtubules, we will use a Drosophila model in which mutants of the LYST counterpart, encoded by the mauve (mv) gene, show enlarged LROs (yolk granules) and microtubule defects in mitosis and in maintaining nuclei at the correct position in the embryo. Mauve co-immunoprecipitates from Drosophila embryos with factors involved in maturation of endosomes; a factor enabling dissociation of the SNARE complex from mature vesicles; Dynein/Dynactin, which have roles in vesicle trafficking and at microtubules; and several centrosome-associated molecules. Thus, this stage of Drosophila development is highly amenable to study the role of LYST/Mauve in the biogenesis of LROs and at microtubules and centrosomes. To establish the role of the Mauve/LYST complex in regulating LRO size and trafficking, we will follow yolk granule biogenesis in wild-type and mv-mutant females; determine the effects of constitutively active and dominant-negative forms of the enodcytotic regulators Rab5, Rab7 and NSF1. To discover the role of Mauve/LYST complex in regulating microtubule dynamics, we will determine microtubule defects in mv- derived embryos and establish the genetic interactions between mv and genes for microtubule associated proteins with which it associates and physical interactions between these gene products. By determining how Mauve directs the centrosomal association of Minispindles protein; how together with Rab5 and Dynein, it promotes accumulation of microtubule associated proteins at the centrosome; and how Mauve's partner proteins participate in recruitment of microtubule organizing molecules at centrosomes we will uncover how vesicle trafficking associated proteins can participate in promoting centrosomal maturation. We anticipate that this will define the dual role of Mauve/LYST in regulating vesicle fission/fusion and in the trafficking of proteins important for microtubule nucleation and centrosome maturation. We anticipate our findings will translate to human cells where they will have potential to unlock doors for the development of therapeutic agents to treat the immunological defects of CHS patients.

项目总结