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Regulation of Synaptic Dysfunction and Maintenance with age using Drosophila

使用果蝇调节突触功能和随年龄的维持

基本信息

批准号：
10670752
负责人：
Daniel T. Babcock
金额：
$ 33.59万
依托单位：
LEHIGH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670752
关键词：
Address Adult Affect Age Aging Amyotrophic Lateral Sclerosis Behavioral Assay Biological Assay Biological Models Bone Morphogenetic Proteins Collection Communication Complex Cytoskeleton Defect Denervation Development Disease Drosophila genus Electrophysiology (science)Event Functional disorder Genes Genetic Genetic Complementation Test Glutamate Receptor Goals Golgi Apparatus Homologous Gene Human Immunohistochemistry Impairment Maintenance Measures Modeling Molecular Monitor Morphology Motor Neurons Muscle Mutation Nerve Degeneration Neurodegenerative Disorders Neuromuscular Junction Pathway interactions Performance Physiological Population Process Proteins Receptor Signaling Regulation Research Role Signal Pathway Signal Transduction Signaling Protein Sorting Structure Synapses Testing Time Transmission Electron Microscopy age related design fighting fly functional disability fused in sarcoma genome wide screen genome-wide in vivo loss of function motor neuron degeneration mutant nervous system disorder neuron loss neuroprotection novel protein expression synaptic function therapeutic target trafficking trans-Golgi Network treatment strategy

项目摘要

Project Summary Although much is known regarding the development of synapses, very little is known about how these complex structures are maintained throughout the aging process. Defects in synaptic communication are responsible for a great number of neurological disorders, and they are associated with the earliest stages of several neurodegenerative diseases. A major hurdle in the field has been the lack of a genetically tractable model system in which to systematically assess synaptic dysfunction over time in vivo. To address this issue, we propose to use Drosophila to examine the structural and functional impairment of synaptic integrity with aging in adult flight muscles. Our guiding hypothesis is that maintaining synaptic structure and function requires a conserved set of genes involved in trans-synaptic signaling, and that disruption of these signaling pathways are among the early deficits in neurological disorders. To test this hypothesis, we propose to pursue three Specific Aims. The first Aim is to identify the mechanisms underlying synaptic dysfunction in mayday mutants, which we previously identified as displaying age-dependent denervation of flight motor neurons. Our second aim is to characterize novel genes associated with synaptic impairment that we identified through a genome-wide screen. Our third Aim is to determine the structural and functional impairment of synapses in a model of Amyotrophic Lateral Sclerosis (ALS). Our proposed research has the potential to reveal the cellular and molecular mechanisms responsible for maintaining synaptic integrity with age, many of which will likely serve as potential therapeutic targets for developing treatment strategies for several neurological disorders.

项目摘要虽然关于突触的发育知道很多，但对这些复合体是如何形成的却知之甚少。结构在整个老化过程中保持不变。突触通讯缺陷是原因之一对于大量的神经紊乱，它们与几种疾病的早期阶段有关神经退行性疾病。这一领域的一个主要障碍是缺乏遗传上易驯服的模型在体内系统地评估随时间推移的突触功能障碍的系统。为了解决这个问题，我们建议使用果蝇来研究结构和功能随着年龄的增长，成人飞行肌肉突触完整性受损。我们的指导性假设是维持突触的结构和功能需要一组保守的涉及跨突触信号的基因，而且这些信号通路的中断是神经系统疾病的早期缺陷之一。为了测试这一点假设，我们提出追求三个具体目标。第一个目标是确定潜在的机制求救突变体的突触功能障碍，我们以前发现这是年龄依赖性的飞行运动神经元的去神经作用。我们的第二个目标是描述与突触相关的新基因我们通过全基因组筛查发现的损伤。我们的第三个目标是确定结构和肌萎缩侧索硬化症(ALS)模型中突触的功能损害我们提出的研究有可能揭示细胞和分子机制随着年龄的增长保持突触的完整性，其中许多可能成为潜在的治疗靶点为几种神经疾病制定治疗策略。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mayday sustains trans-synaptic BMP signaling required for synaptic maintenance with age.

随着年龄的增长，"五月天 "能维持突触维持所需的跨突触 BMP 信号。

DOI：
10.7554/elife.54932
发表时间：
2021-03-05
期刊：
eLife
影响因子：
7.7
作者：
Sidisky JM;Weaver D;Hussain S;Okumus M;Caratenuto R;Babcock D
通讯作者：
Babcock D

Vexed mutations promote degeneration of dopaminergic neurons through excessive activation of the innate immune response.

DOI：
10.1038/s41531-022-00417-5
发表时间：
2022-11-02
期刊：
NPJ PARKINSONS DISEASE
影响因子：
8.7
作者：
Davis, Jacinta;Kolaski, Elizabeth;Babcock, Daniel T.
通讯作者：
Babcock, Daniel T.

Characterizing dopaminergic neuron vulnerability using genome-wide analysis.

DOI：
10.1093/genetics/iyab081
发表时间：
2021-08-09
期刊：
Genetics
影响因子：
3.3
作者：
Davis J;Da Silva Santos C;Zavala NC;Gans N;Patracuolla D;Fehrenbach M;Babcock DT
通讯作者：
Babcock DT

Genome-wide analysis reveals novel regulators of synaptic maintenance in Drosophila.

DOI：
10.1093/genetics/iyad025
发表时间：
2023-04-06
期刊：
GENETICS
影响因子：
3.3
作者：
Sidisky, Jessica M.;Moreira, Danielle de Paula;Okumus, Meryem;Caratenuto, Russell;Drost, Cassidy;Connors, Bali;Hussain, Sarrah;Alkhatib, Stephanie;Babcock, Daniel T.
通讯作者：
Babcock, Daniel T.

Visualizing Synaptic Degeneration in Adult Drosophila in Association with Neurodegeneration.