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Mechanisms of Regeneration: Facial Nerve Injury and Repair

再生机制：面神经损伤与修复

基本信息

批准号：
10013199
负责人：
Jon-Paul Pepper
金额：
$ 16.65万
依托单位：
STANFORD 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：
2019-09-09 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10013199
关键词：
Action Potentials Adult Affect Agonist Alleles Angiogenic Factor Antibodies Axon Cell physiology Cells Clinical Contralateral Data Development Dissection Electrophysiology (science)Elements Erinaceidae Event Eye Face Facial Nerve Injuries Facial nerve structure Facial paralysis Fibroblasts Fibrosis Gene Cluster Gene Expression Profiling Genes Genetic Genetic Transcription Glioma Immunofluorescence Immunologic Immunohistochemistry Impairment Injury Label Ligands Measures Mediator of activation protein Mentors Messenger RNA Modeling Molecular Motor Neurons Movement Mus Muscle Natural regeneration Nerve Nerve Regeneration Nerve Tissue Neural Crest Neurons Oncogenes Operative Surgical Procedures Oral Otolaryngology Paralysed Pathway interactions Patients Perineuriums Pharmacology Physicians Play Population Positioning Attribute Program Development Quality of life Recovery Research Role SHH gene Schwann Cells Scientist Source Speech Stains Supervision Tamoxifen Time Tissues Training Transgenic Organisms United States Vibrissae Western Blotting Work angiogenesis base career development clinically significant disability effective therapy experience experimental study gain of function improved in vivo injured injury and repair innovation intraperitoneal medical schools nerve injury nerve transection new therapeutic target next generation sequencing novel therapeutic intervention professor response response to injury screening skills smoothened signaling pathway spatiotemporal therapeutic target transcriptome sequencing

项目摘要

Project Summary/Abstract This proposal presents a five-year research career development program focused on the study of Hedgehog (Hh) pathway signaling in facial nerve injury response. The candidate is currently an Assistant Professor of Otolaryngology at the Stanford School of Medicine. The outlined proposal builds on the candidate’s previous research and clinical experience under the supervision of a world-renowned expert in Hh pathway signaling, Dr. Phil Beachy. The proposed experiments and didactic work will position the candidate with a unique set of skills that will enable his transition to independence as a physician scientist in the mechanisms of nerve injury response and nerve fibrosis. Facial paralysis results in significant disability for affected patients, impacting both facial function and overall quality of life. For patients with permanent paralysis, surgery is the most effective treatment to improve facial symmetry and – in some cases – restore partial movement. However, existing treatments do not completely restore normal facial movement. Clinically, the injured facial nerve becomes fibrotic, which can impede recovery and treatment. Despite the clinical importance of this, the mechanism underlying nerve fibrosis is poorly understood. Given the critical role of the hedgehog pathway in perineurial development, we explored the function of hedgehog-responsive elements in the murine facial nerve after injury. We first verified the presence of hedgehog-responsive fibroblasts (Gli1+) within the murine facial nerve. Gli1+ fibroblasts within the facial nerve expand impressively after injury and compose the majority of the perineurium of the regenerating nerve. These cells closely associate with activated Schwann cells and regenerating axons and appear to promote angiogenesis in the first two weeks after injury. By 10 weeks after injury, however, Gli1+ fibroblasts appear to form fibrotic tissue within the nerve. Following on these findings, we hypothesize that Hh signaling promotes early nerve regeneration after injury but transitions to a pro-fibrotic state at later time points after injury. To assess these hypotheses, we propose the following aims: 1) Characterize the role of Hh signaling after facial nerve injury using powerful genetic and pharmacologic models, 2) Describe changes in Gli1+ cells during facial nerve regeneration and fibrosis via Next Generation Sequencing. Completion of the research in this proposal will enable a thorough dissection of the role of Hh signaling in facial nerve injury, vet this pathway as a mediator of both regeneration and fibrosis after injury, and reveal new therapeutic targets for clinical use.

项目总结/文摘