Engineering protease biomarkers to guide surgical therapy for vestibular schwannoma and Neurofibromatosis Type 2

工程蛋白酶生物标志物指导前庭神经鞘瘤和 2 型神经纤维瘤病的手术治疗

基本信息

批准号：
10571125
负责人：
Yin Ren
金额：
$ 19.18万
依托单位：
OHIO STATE UNIVERSITY
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：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10571125
关键词：
Acoustic Neuroma Adhesions Advisory Committees Animal Model Architecture Area Behavior Benign Biological Biological Markers Biology Brain Brain Injuries Brain Neoplasms Brain Stem Cell Line Cell model Cells Central Nervous System Cessation of life Classification Cochlea Communication Convection Cranial Nerves Craniotomy Cues Cystic Neoplasm Data Disease Dissection Educational workshop Engineering Excision Extracellular Matrix FDA approved Face Facial Injuries Facial paralysis Fluorescence Resonance Energy Transfer Foundations Future Gelatinase A Gelatinase B Genomics Goals Growth Hearing Home Human Impairment Incidence Intracranial Neoplasms K-Series Research Career Programs Label Libraries MMP14 gene Matrix Metalloproteinases Mentors Mentorship Metalloproteases Methods Morbidity - disease rate Mus Nanotechnology Nature Nerve Nervous System Neoplasms Neurilemmoma Neurofibromatosis 2 Neurologic Ohio Operative Surgical Procedures Outcome Paralysed Patient-Focused Outcomes Patients Pattern Penetration Peptide Hydrolases Peptides Pharmaceutical Preparations Pharmacotherapy Physicians Play Principal Investigator Prognostic Marker Research Risk Role Scientist Sensitivity and Specificity Serum Specificity Surgeon Survival Rate Syndrome Testing Therapeutic Tissues Training Translating Translational Research Tumor Suppressor Genes Tumor Tissue Universities Visual Visualization Work Xenograft Model Xenograft procedure angiogenesis bilateral vestibular Schwannoma biomarker identification career cell motility deafness design disease classification gene function genomic data hearing impairment high throughput screening improved improved outcome in vivo innovation molecular marker mouse model multidisciplinary nanomaterials nanoparticle nanoparticle delivery neoplastic cell novel diagnostics novel therapeutics overexpression point of care preservation safe patient skull base surgery outcome systems research tool transcriptome sequencing transcriptomic profiling transcriptomics tumor tumor growth

项目摘要

ABSTRACT Neurofibromatosis type 2 (NF2) is a profoundly devastating tumor predisposing syndrome characterized by multiple nervous system tumors that cause substantial debility for patients. The hallmark of NF2 is bilateral vestibular schwannomas (VS) which cause hearing loss, imbalance, brainstem compression and even death. Both NF2-associated and sporadic VS can develop aggressive cystic degeneration which result in rapid neurologic decline. There are no FDA-approved pharmacotherapies against cystic VS and surgery is the only treatment. However, surgical outcomes are highly variable, and surgery carries considerable morbidities including deafness, facial paralysis, brain injury and incomplete resection, due to significant peri-tumoral adhesions and reliance on imprecise visual cues during tumor dissection. Efforts are needed to identify biomarkers to classify aggressive VS and develop intraoperative tools to detect tumor cells, visualize the interface between tumor and cochlear/facial cranial nerves and improve the accuracy of surgical resection. This K08 career development award is designed to launch the principal investigator’s career as an independent surgeon scientist, whose goal is to understand mechanisms that underlie VS growth and cystic degeneration, identify molecular biomarkers to classify disease, and leverage nanotechnology tools to improve the precision of tumor surgery. The PI’s mentor (Krystof Bankiewicz) is a leader in delivering therapeutics to the central nervous system and translational research. The PI’s co-mentor (Long-Sheng Chang) is an expert in studying the NF2 tumor suppressor gene function in VS. Additional mentorship is provided by a research advisory committee of experts in nanoparticle delivery (Yizhou Dong), matrix metalloprotease and extracellular matrix biology (Jennifer Leight), and skull base surgery (Oliver Adunka), along with didactics and workshops at the Ohio State University and nationally. Previously, the PI utilized primary human VS cultures to develop nanoparticles that target VS and identified a matrix metalloproteinase whose activity was associated with poor surgical outcomes in VS. The proposed study will: 1) systematically identify proteases dysregulated in VS through spatial transcriptomic profiling; 2) engineer a library of nanomaterials to rapidly quantify VS protease activity and establish an activity-based tumor-classifying biomarker; 3) develop protease-sensing, tumor-targeted nanoparticles. Results from this work will elucidate mechanisms that regulate VS behavior and establish tools to enhance the accuracy of surgical resection, which could ultimately reduce treatment-associated morbidity, preserve cranial nerve function and improve outcomes for patients with this devastating disease. Furthermore, the principal investigator will obtain the training needed to transition into an independent physician scientist focusing on using nanotechnology to translate biological discoveries into new diagnostics and therapeutics for VS and NF2.

抽象的 2型神经纤维瘤病（NF2）是一种易受破坏性的肿瘤易感性综合征，其特征是多个神经系统肿瘤对患者产生大量依赖性。 NF2的标志是双边前庭schwannomas（VS）会导致听力损失，失衡，脑干压缩甚至死亡。 NF2相关和零星vs均可发展侵袭性囊性变性，从而迅速神经系统下降。没有针对囊性与手术的FDA批准的药物治疗是唯一的治疗。但是，手术结局高度可变，手术伴有相当大的病毒包括死亡性，面部麻痹，脑损伤和不完全切除，这是由于明显的肌周围肿瘤解剖过程中粘附和依赖不可固定的视觉提示。需要努力来识别生物标志物对攻击性VS进行分类并开发术中工具以检测肿瘤细胞，可视化肿瘤与人工耳蜗/面部颅神经之间的接口并提高手术切除的准确性。该K08职业发展奖旨在启动首席调查员的职业独立外科医生科学家，其目标是了解基于增长和囊性的机制退化，确定分子生物标志物以对疾病进行分类，并利用纳米技术工具来改进肿瘤手术的精度。 PI的心理（Krystof Bankiewicz）是提供治疗的领导者中枢神经系统和转化研究。 PI的Co-Mentor（Long-Sheng Chang）是专家研究VS中的NF2肿瘤抑制基因功能。一项研究提供了其他精神纳米颗粒交付专家咨询委员会（Yizhou Dong），基质金属蛋白酶和细胞外基质生物学（Jennifer Leight）和Skull Base Surgery（Oliver Adunka），以及教学和讲习班俄亥俄州立大学和全国。以前，PI利用原代人与培养物来开发针对并确定的纳米颗粒一种基质金属蛋白酶，其活性与VS中的手术结局差有关。提议研究将：1）系统地识别通过空间转录组分析在VS中失调的蛋白酶； 2）设计纳米材料的库，以快速量化与蛋白酶活性并建立基于活动的蛋白酶活性肿瘤分类生物标志物； 3）发展蛋白酶感应，靶向肿瘤的纳米颗粒。结果工作将阐明规范行为的机制，并建立工具以提高其准确性手术切除最终可以减少与治疗相关的发病率，保留颅神经这种毁灭性疾病患者的功能和改善结果。此外，校长调查人员将获得过渡到独立的物理科学家所需的培训，专注于使用纳米技术将生物学发现转化为VS和NF2的新诊断和治疗。