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

基本信息

批准号：
8738734
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
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-20 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8738734
关键词：
Adult Affect Age Aging Alzheimer&apos 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 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 prevent professor public health relevance reinnervation repaired research study response skills stem therapeutic development trafficking

项目摘要

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 Research Institute的终身助理助理教授。该研究所的跨学科，互动，大学和养育氛围确实有利于发展成功的研究和学术生涯。为了帮助我的职业目标，我与迈克尔·弗里德兰德（Michael Friedlander）博士（在VTCRI）一起召集了一支杰出的导师团队，并担任导师，肯尼斯·菲斯贝克（Kenneth Fischbeck）博士（在Ninds）和迈克尔·福克斯（Michael Fox）（在VTCRI）担任联合主管。在短期内，我将获得进一步的培训，获得新技能以及成功运行团队驱动的研究项目所需的经验，并竞争包括R01在内的独立资金来源。这些经验将为我提供获得任期所需的基础，并经营着一个非常成功且资金充足的实验室。在我的实验室中，我将寻求发现和操纵以维持突触的作用的分子，从而防止正常衰老随着正常衰老而发生的运动技能的下降，并使多种与年龄相关的神经退行性疾病的影响。在该提案中，我假设维持神经肌肉连接的正常功能（NMJ），在运动神经元和肌肉纤维之间形成的大型且实验可及的突触可以足以减慢或防止由衰老和amiytrophic sclerophic sclerisos（ALS）引起的运动技能侵蚀。这一假设源于以下事实：NMJ处的有害变化似乎是在正常衰老和ALS的进展过程中运动神经元死亡和肌肉纤维萎缩之前的死亡。在这方面，我收集了初步数据，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）可能是有希望的候选分子，可以保护NMJ，以保护NMJ免受正常衰老的损害。在小鼠中，FGF-22的缺失导致NMJ过早衰老。它还延迟了受伤后骨骼肌的加剧。同样，FGFBP1的减少延迟了骨骼肌的加剧。因此，这些结果表明FGF-22和FGFBP1可以起作用来修复NMJ。在这个项目中，我的目标是研究这些增长的功能 NMJ衰老的因素以及ALS的启动和进展。除了训练机会外，拟议的实验还可能导致新的治疗靶标和保护运动系统的方法。