Role of Target-derived FGFs in Maintaining and Repairing Synapses

靶标衍生的 FGF 在维持和修复突触中的作用

• 批准号: 8896083
• 负责人: Gregorio Valdez
• 金额: $ 22.64万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896083
• 关键词: Adult; Affect; Age; Aging; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animals; Architecture; Atrophic; Axon; Basal lamina; Belief; Binding; Binding Proteins; Biological; Biotin; Brain; Brain Diseases; Caring; Cell Nucleus; Cessation of life; Data; Defect; Development; Disease; Embryo; Etiology; Fibroblast Growth Factor; Foundations; Foxes; Funding; Funding Agency; Goals; Government; Growth Factor; Health; Individual; Injury; Institutes; Laboratories; Lead; Ligands; Maintenance; Medical; Mentors; Molecular; Motor; Motor Neurons; Motor Skills; Mus; Muscle; Muscle Fibers; Myopathy; National Institute of Neurological Disorders and Stroke; Nerve; Neurodegenerative Disorders; Neuromuscular Junction; Peptides; Premature aging syndrome; Publishing; Quality of life; Research; Research Institute; Research Project Grants; Resources; Role; Running; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; Spinal; Synapses; System; Testing; Therapeutic; Training; Virginia; age related; career; design; experience; glycosylation; keratinocyte growth factor; member; motor deficit; mouse model; muscle aging; neuron loss; new therapeutic target; normal aging; novel; overexpression; planetary Atmosphere; presynaptic; presynaptic neurons; prevent; professor; reinnervation; repaired; research study; response; skills; stem; therapeutic development; trafficking

DESCRIPTION (provided by applicant): I am a tenure-track assistant professor at the Virginia Tech Carilion Research Institute. The interdisciplinary, interactive, collegial and nurturing atmosphere at the institute is truly conducive for developing a successful research and academic career. To help with my career goals, I have assembled an exceptional team of mentors, with Dr. Michael Friedlander (at VTCRI) serving as a mentor and Dr. Kenneth Fischbeck (at NINDS) and Dr. Michael Fox (at VTCRI) serving as co-mentors. In the short-term, I will obtain further training, acquire new skills and the experience needed to successfully run a team-driven research project and compete for independent sources of funding, including an R01. These experiences will provide me with the foundation necessary to obtain tenure and run a highly successful and well-funded laboratory. In my laboratory, I will seek to discover and manipulate molecules that act to maintain synapses, and thereby prevent the decline of motor skills that occur with normal aging and in blunting the effects of a multitude of age-related neurodegenerative diseases. In this proposal, I hypothesize that maintaining the normal function of the neuromuscular junction (NMJ), a large and experimentally accessible synapse formed between motor neurons and muscles fibers could be sufficient to slow or prevent the erosion of motor skills caused by aging and amyotrophic lateral sclerosis (ALS). This hypothesis stems from the fact that deleterious changes at the NMJ appears to precede death of motor neurons and atrophy of muscle fibers during the progression of normal aging and ALS. In this regard, I have gathered preliminary data suggesting that three members of the fibroblast growth factor (FGF) signaling pathway, FGF-7/10/22, and a FGF-binding protein (FGFBP1) could be promising candidate molecules for protecting NMJs from insults emanating from normal aging and ALS. In mice, deletion of FGF- 22 results in premature aging of the NMJ. It also delays reinnervation of skeletal muscles after injury. Similarly, a reduction in FGFBP1 delays reinnervation of skeletal muscles. Thus, these results suggest that FGF-22 and FGFBP1 could function to repair the NMJ. In this project, my goal is to investigate the function of these growth factors in aging NMJs and in the initiation and progression of ALS. In addition to the training opportunities, the proposed experiments could lead to new therapeutic targets and approaches for protecting the motor system.

描述（由申请人提供）：我是弗吉尼亚理工大学 Carilion 研究所的终身教授助理教授。该研究所的跨学科、互动、学院和培育氛围确实有利于发展成功的研究和学术生涯。为了帮助我实现职业目标，我组建了一支出色的导师团队，其中迈克尔·弗里德兰德博士（VTCRI）担任导师，肯尼思·菲施贝克博士（NINDS）和迈克尔·福克斯博士（VTCRI）担任合伙人-导师。在短期内，我将获得进一步的培训，获得成功运行团队驱动的研究项目所需的新技能和经验，并竞争独立的资金来源，包括 R01。这些经验将为我获得终身教职和运营一个非常成功且资金充足的实验室提供必要的基础。在我的实验室中，我将寻求发现和操纵维持突触的分子，从而防止正常衰老过程中出现的运动技能下降，并减弱多种与年龄相关的神经退行性疾病的影响。在这个提议中，我假设维持神经肌肉接头（NMJ）的正常功能，即运动神经元和肌肉纤维之间形成的一个大的、实验上可访问的突触，可能足以减缓或防止由衰老和肌萎缩侧索硬化引起的运动技能的侵蚀。硬化症（ALS）。这一假设源于这样一个事实：在正常衰老和 ALS 的进展过程中，NMJ 的有害变化似乎先于运动神经元死亡和肌纤维萎缩。在这方面，我收集的初步数据表明，成纤维细胞生长因子 (FGF) 信号通路的三个成员 FGF-7/10/22 和 FGF 结合蛋白 (FGFBP1) 可能是保护 NMJ 免受影响的有希望的候选分子。正常衰老和 ALS 引起的损伤。在小鼠中，FGF-22 的缺失会导致 NMJ 过早衰老。它还会延迟受伤后骨骼肌的神经再生。同样，FGFBP1 的减少会延迟骨骼肌的神经支配。因此，这些结果表明 FGF-22 和 FGFBP1 可以发挥修复 NMJ 的作用。在这个项目中，我的目标是研究这些生长的功能 NMJ 老化以及 ALS 发生和进展的因素。除了培训机会之外，拟议的实验还可以带来新的治疗目标和保护运动系统的方法。

项目成果

Degeneration of proprioceptive sensory nerve endings in mice harboring amyotrophic lateral sclerosis-causing mutations.

• DOI: 10.1002/cne.23848
• 发表时间: 2015-12-01
• 期刊: The Journal of comparative neurology
• 作者: Vaughan SK;Kemp Z;Hatzipetros T;Vieira F;Valdez G
• 通讯作者: Valdez G

Impact of Aging on Proprioceptive Sensory Neurons and Intrafusal Muscle Fibers in Mice.

衰老对小鼠本体感觉神经元和梭内肌纤维的影响。

• DOI: 10.1093/gerona/glw175
• 发表时间: 2017
• 期刊: The journals of gerontology. Series A, Biological sciences and medical sciences
• 作者: Vaughan,SydneyK;Stanley,OliviaL;Valdez,Gregorio
• 通讯作者: Valdez,Gregorio

Muscle Fibers Secrete FGFBP1 to Slow Degeneration of Neuromuscular Synapses during Aging and Progression of ALS.

肌肉纤维分泌 FGFBP1 以减缓衰老和 ALS 进展过程中神经肌肉突触的退化。

• DOI: 10.1523/jneurosci.2992-16.2016
• 发表时间: 2017
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Taetzsch,Thomas;Tenga,MilagrosJ;Valdez,Gregorio
• 通讯作者: Valdez,Gregorio