Tumor-Mediated Hearing Loss in Neurofibromatosis Type II

II 型神经纤维瘤病中肿瘤介导的听力损失

基本信息

批准号：
10531225
负责人：
Christine Thuyvan Dinh
金额：
$ 16.58万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10531225
关键词：
Acoustic Neuroma Address Affect Algorithms Antibodies Area Auditory Bioinformatics Biometry Blood Candidate Disease Gene Cell Culture Techniques Cell Death Cells Central Nervous System Neoplasms Cerebrospinal Fluid Child Code Collection Communication Cytokine Receptors DNA Sequence Alteration Data Development Disease Epigenetic Process Family Florida Gene Mutation Genes Genetic Genetic Transcription Genotype Goals Hair Cells Hearing Hereditary Disease Human Human Genetics Immunologic Deficiency Syndromes Individual Inflammation Inflammatory Inflammatory Response Inherited Interleukin-6 Investigation Life Link Location Long-Term Effects Malignant Neoplasms Mediating Mentors Methylation Monitor Monozygotic twins Mutate Mutation National Institute on Deafness and Other Communication Disorders Neonatal Nerve Neurilemmoma Neurofibromatosis 2 Neurofibromin 2 Neurosciences Operative Surgical Procedures Organ of Corti Otolaryngology Pathway Analysis Pathway interactions Patients Phenotype Polymerase Chain Reaction Proteins Quality of life Rattus Research Research Training Role Schedule Scientist Signal Transduction Structure TNF gene Testing Training Training Programs Training Support Translational Research Tumor Bank Tumor Burden Tumor Suppressor Genes Universities Western Blotting Work Xenograft Model bilateral vestibular Schwannoma bisulfite sequencing career development clinical database clinical investigation cytokine drug testing effective therapy experimental study extracellular hearing impairment hearing preservation interest lectures methylation pattern novel novel therapeutics ototoxicity patient safety patient stratification personalized medicine pre-clinical precision medicine professor programs prospective protein expression protein function theories therapeutic target transcriptome sequencing tumor tumor heterogeneity tumorigenesis whole genome young adult

项目摘要

ABSTRACT Goal: The goal of this application is to provide a structured research training program under mentors in related fields to promote the development of the applicant into an independent clinician-scientist investigating Neurofibromatosis Type II (NF2) and hearing-related disorders. The career development aims of this application are to support training in genetic and epigenetic research, incorporating important aspects of bioinformatics and biostatistics, to support the applicant’s pathway to independence. This will be accomplished through coordinated efforts in the University of Miami Department of Otolaryngology and Hussman Institute of Human Genetics (HIHG) and the Division of Neuroscience at University of Central Florida. Research Program: NF2 is a hereditary tumor disorder that predisposes children and young adults to develop multiple central nervous system tumors, particularly bilateral vestibular schwannomas (VS) that cause hearing loss (HL), imbalance, and life-threatening intracranial complications. VS occur along the cochleovestibular nerve and are caused by mutations in the NF2 tumor suppressor gene that encodes merlin protein. Although the mechanisms of tumorigenesis are known, the factors that cause tumor-mediated HL in NF2 are not well understood, thereby impeding progress in identifying effective therapies that reduce tumor burden and preserve hearing. Our interest in determining tumor-mediated mechanisms of HL has led us to the novel finding that VS demonstrate differentially methylated regions in genes of inflammatory response in patients with and without HL. Our central hypothesis is that alterations of the genomic and epigenetic profiles in VS result in aberrant changes in pro-inflammatory signaling that cause tumor-mediated HL in NF2 patients. For this work, we have developed: (1) a unique tumor bank of human VS, (2) primary human VS cell cultures, (3) an immunodeficient rat xenograft model of VS that develops HL, and (4) a clinical database. The experiments proposed here will define the role of tumor genetics and epigenetics on the expression and secretion of proinflammatory cytokines and the development of HL, which are essential steps towards establishing personalized treatments for NF2. Training Program: The applicant will participate in formal didactic lectures and hands-on training through the Master’s Program in Clinical and Translational Investigations at the University of Miami, supplementary informal didactic lectures and seminars, and one-on-one tutorials with her mentors and collaborators. She will also attend regularly scheduled intellectual activities in the Otolaryngology Department and HIHG and meet frequently with advisors to monitor her progress. Dr. Xue-Zhong Liu, Director of the Miami Otogenetic Program, and Dr. Cristina Fernandez-Valle, Professor of Neuroscience, will serve as mentors.

抽象的目标：该应用的目标是在相关的导师下提供一个结构化的研究培训计划领域以促进申请人的发展为独立的临床科学家调查 II型神经纤维瘤病（NF2）和与听力有关的疾病。该应用程序的职业发展目标支持遗传和表观遗传学研究的培训，影响生物信息学的重要方面生物统计学，以支持申请人的独立途径。这将通过协调来实现在迈阿密大学耳鼻喉科学系和侯斯曼人类遗传学研究所的努力（HIHG）和佛罗里达大学中央大学的神经科学系。研究计划：NF2是一种遗传性肿瘤疾病，使儿童和年轻人易于发展多个中枢神经系统肿瘤，尤其是双侧前庭造型瘤（VS）损失（HL），失衡和威胁生命的颅内并发症。 vs沿着耳目肉神经并由编码Merlin蛋白的NF2肿瘤抑制基因中的突变引起。虽然肿瘤发生的机制是已知的，导致NF2中肿瘤介导的HL的因素不好理解，因此阻碍了识别减少肿瘤燃烧和保存的有效疗法的进展听力。我们对确定HL肿瘤介导的机制的兴趣使我们达到了新发现，即在患有和没有HL的患者中，在炎症反应基因中表现出不同的甲基化区域。我们的中心假设是，基因组和表观遗传谱的改变VS导致异常 NF2患者导致肿瘤介导的HL的促炎信号传导的变化。对于这项工作，我们已经开发了：（1）独特的人类肿瘤库，（2）原代人与细胞培养物，（3）开发HL的免疫缺陷大鼠异种移植模型，以及（4）临床数据库。实验这里提出的将定义肿瘤遗传学和表观遗传学在表达和分泌方面的作用促炎细胞因子和HL的发展，这是建立的重要步骤 NF2的个性化治疗方法。培训计划：申请人将通过迈阿密大学临床和翻译调查的硕士课程，补充非正式教学讲座和下水道，以及与她的导师和合作者一对一的教程。她也会参加通常在耳鼻喉科部门和HIHG中进行的智力活动，并经常与监视她的进度的顾问。迈阿密耳遗传学计划主任Xue-Zhong Liu博士和克里斯蒂娜博士神经科学教授Fernandez-Valle将担任导师。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

RAD51 Inhibitor and Radiation Toxicity in Vestibular Schwannoma.

DOI：
10.1177/01945998221083506
发表时间：
2022-11
期刊：
Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery
影响因子：
0
作者：
通讯作者：

Fluorescent Detection of Vestibular Schwannoma Using Intravenous Sodium Fluorescein In Vivo.

DOI：
10.1097/mao.0000000000002988
发表时间：
2021-04-01
期刊：
Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology
影响因子：
0
作者：
Szczupak M;Peña SA;Bracho O;Mei C;Bas E;Fernandez-Valle C;Liu XZ;Telischi FF;Ivan M;Dinh CT
通讯作者：
Dinh CT

CUDC907, a dual phosphoinositide-3 kinase/histone deacetylase inhibitor, promotes apoptosis of NF2 Schwannoma cells.

DOI：
10.18632/oncotarget.28254
发表时间：
2022
期刊：
ONCOTARGET
影响因子：
0
作者：
Huegel, Julianne;Dinh, Christine T;Martinelli, Maria;Bracho, Olena;Rosario, Rosa;Hardin, Haley;Estivill, Michael;Griswold, Anthony;Gultekin, Sakir;Liu, Xue-Zhong;Fernandez-Valle, Cristina
通讯作者：
Fernandez-Valle, Cristina

Understanding the Radiobiology of Vestibular Schwannomas to Overcome Radiation Resistance.

DOI：
10.3390/cancers13184575
发表时间：
2021-09-12
期刊：
Cancers
影响因子：
5.2
作者：
Thielhelm TP;Goncalves S;Welford SM;Mellon EA;Cohen ER;Nourbakhsh A;Fernandez-Valle C;Telischi F;Ivan ME;Dinh CT
通讯作者：
Dinh CT

Effect of AR42 in Primary Vestibular Schwannoma Cells and a Xenograft Model of Vestibular Schwannoma.

DOI：
10.1097/mao.0000000000003556
发表时间：
2022-07-01
期刊：
Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology
影响因子：
0
作者：
Misztal C;Bracho O;Bas E;Estivill M;Ivan ME;Morcos J;Bhatia R;Telischi F;Liu XZ;Gultekin SH;Fernandez-Valle C;Dinh CT
通讯作者：
Dinh CT