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GENETICS OF ENDOCYTIC TRAFFICKING IN THE DROSOPHILA EYE

果蝇眼睛内吞转运的遗传学

基本信息

批准号：
10680753
负责人：
Helmut J Kramer
金额：
$ 41万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680753
关键词：
Acinus organ component Address Adult Alternative Splicing Autophagocytosis Autophagosome Bacteria Biochemical Biological Calibration Cell physiology Cells Communicable Diseases Cytoplasm Data Drosophila eye Drug Targeting Energy Supply Eye FRAP1 gene Functional disorder Genes Genetic Goals Grant Growth Interruption Invaded Light Link Longevity Lysosomes Macular degeneration Malignant Neoplasms Mammalian Cell Measures Membrane Metabolic Metabolic stress Metabolism Mitochondria Modeling Molecular Mutation Nerve Degeneration Nervous System Neurons Organelles Oxidative Stress Pathway interactions Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Photoreceptors Physiological Physiology Post-Translational Protein Processing Process Proteins Quality Control Research Role Signal Pathway Signal Transduction Sirolimus Starvation Stress Testing Time Toxic effect Visual System Work Yeasts age related analog biological adaptation to stress inhibition of autophagy interest mTOR inhibition mutant pharmacologic photoreceptor degeneration protein activation protein aggregation protein function proteostasis response side effect trafficking

项目摘要

Neurons in adults are essentially irreplaceable and especially vulnerable to the accumulation of protein aggregates, dysfunctional mitochondria, and similarly distractive agents. The most important pathway available to neurons to limit such damage is autophagy. This pathway, initially described in the context of the mTor-regulated starvation-induced metabolic rescue pathway in yeast and mammalian cells, is initiated by the formation of an isolation membrane followed by its expansion, the engulfment of cytoplasmic content into a closed autophagosome and its fusion to the lysosomes and degradation of autophagosomal content. Beyond its importance in the starvation response, starvation and mTor-independent autophagy is increasingly recognized as an important quality control mechanism that reduces degeneration of neurons and photoreceptor cells and has implications for cancer and infectious diseases. Therefore, the distinct cellular signaling pathways that adjust the rate of autophagy to the cell’s physiology are important to understand. Because excessive autophagy is lethal to cells, the different signaling pathways inducing autophagy must be careful coordinated and calibrated. For one such pathway, the Acinus protein is as a critical regulator. The Acinus protein integrates signals from multiple pathways to modulate the function of core autophagy proteins and stimulate the induction of starvation-independent autophagy. This grant aims to understand the molecular mechanisms that regulate the levels of Acn protein and its activity. For this purpose, in Aim 1, we propose to define upstream regulators of Acinus including the phosphatases and kinases responsible for regulating its activity and explore their potential as possible drug targets. In Aim 2, we will analyze the mechanistic link between Acinus and its effector Atg1, the master regulatory kinase of the autophagy pathway. In Aim 3, we will explore physiological consequences of disrupting the Acn-Atg1 signaling module in the context of visual system.

成年人的神经元基本上是不可替代的，特别容易受到蛋白质聚集体的积累，功能失调的线粒体，以及类似的分心剂.神经元限制这种损伤的最重要途径是自噬这一途径最初在mTOR调节的细胞内表达。酵母和哺乳动物细胞中饥饿诱导的代谢救援途径启动通过隔离膜的形成，随后其膨胀，细胞质内容物进入封闭的自噬体并融合到溶酶体，自噬体含量的降解。除了在饥荒中的重要性，反应、饥饿和不依赖mTOR的自噬越来越被认为是一种重要的质量控制机制，减少神经元的退化，光感受器细胞，并与癌症和传染病有关。因此，我们认为，不同的细胞信号通路调节自噬的速率，生理学是很重要的。因为过度的自噬对细胞是致命的，诱导自噬的不同信号通路必须仔细协调，已校准。对于一个这样的途径，腺泡蛋白是作为一个关键的调节器。的腺泡蛋白整合多途径信号调节核心功能自噬蛋白和刺激诱导饥饿非依赖性自噬。该基金旨在了解调节痤疮水平的分子机制，蛋白质及其活性。为此，在目标1中，我们建议定义上游腺泡的调节因子，包括负责调节其活性并探索其作为可能药物靶点的潜力。在第二章中，我们将分析腺泡与其效应子Atg 1（主调节激酶）之间的机制联系自噬途径的一部分。在目标3中，我们将探讨在视觉系统中破坏Acn-Atg 1信号模块。