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

• 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
• 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

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.

摘要 神经纤维瘤病2型（NF 2）是一种严重破坏性的肿瘤易感综合征，其特征在于： 多发性神经系统肿瘤，导致患者严重虚弱。NF 2的特征是双侧性的， 前庭神经鞘瘤（VS）可导致听力损失、失衡、脑干压迫甚至死亡。 NF 2相关和散发性VS均可发展为侵袭性囊性变性，导致快速 神经功能衰退没有FDA批准的药物治疗囊性VS和手术是唯一的 治疗然而，手术的结果是高度可变的，手术带来相当大的发病率 包括耳聋，面瘫，脑损伤和不完全切除，由于显着的肿瘤周围 粘连和依赖于不精确的视觉提示。需要努力查明 生物标志物对侵袭性VS进行分类，并开发术中工具来检测肿瘤细胞， 肿瘤与耳蜗/面脑神经的界面，提高手术切除的准确性。 K 08职业发展奖旨在启动首席研究员的职业生涯， 独立的外科医生科学家，其目标是了解VS生长和囊性变的基础机制， 退化，识别分子生物标志物来分类疾病，并利用纳米技术工具来改善 肿瘤手术的精确度PI的导师（Bankiewicz的Kendy）是提供治疗的领导者， 中枢神经系统和转化研究。PI的共同导师（张龙胜）是一位专家， 研究NF 2肿瘤抑制基因在VS中的功能。 纳米颗粒递送专家咨询委员会（董一舟），基质金属蛋白酶和细胞外 矩阵生物学（詹妮弗·莱特）和颅底外科（奥利弗·阿顿卡），沿着教学法和讲习班， 俄亥俄州州立大学和全国。 以前，PI利用原代人VS培养物开发靶向VS的纳米颗粒，并鉴定 一种基质金属蛋白酶，其活性与VS的不良手术结果相关。 研究将：1）通过空间转录组学分析系统地鉴定VS中失调的蛋白酶; 2） 设计一个纳米材料库，以快速量化VS蛋白酶活性，并建立基于活性的 肿瘤分类生物标志物; 3）开发蛋白酶传感、肿瘤靶向纳米颗粒。结果从这个 工作将阐明调节VS行为的机制，并建立工具，以提高准确性， 手术切除，这可能最终降低治疗相关的发病率，保留颅神经 为患有这种毁灭性疾病的患者提供功能和改善结果。此外，校长 研究者将获得转变为独立医生科学家所需的培训，重点是 利用纳米技术将生物学发现转化为VS和NF 2的新诊断和治疗方法。