权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

DNA Methylation and gene expression variations influence pituitary adenoma hormonal function and invasive growth

DNA 甲基化和基因表达变异影响垂体腺瘤激素功能和侵袭性生长

基本信息

批准号：
10224739
负责人：
Gabriel Zada
金额：
$ 51.03万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
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：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224739
关键词：
Acromegaly Address Affect Behavior Benign Brain CRISPR/Cas technology Candidate Disease Gene Cell Culture Techniques Cell Line Cell Survival Cessation of life Chronic Classification Classification Scheme Cluster Analysis Complement DNA DNA Methylation DNA Sequence Alteration DNA methylation profiling Data Deterioration Development Diagnosis Diagnostic Disease Disease remission Dura Mater Epigenetic Process Exhibits Formalin Freezing Gene Expression Gene Expression Alteration Gene Expression Profile Gene Expression Profiling Gene Mutation Gene Silencing Genes Genome Genomics Goals Growth Hormonal Hormone secretion Hormones Human Hypopituitarism In Vitro Institutional Review Boards Intracranial Neoplasms Knowledge Location Methodology Methods Modality Molecular Neurologic Neurologic Deficit Operative Surgical Procedures Outcome Paraffin Embedding Pathway interactions Patients Pharmaceutical Preparations Phenotype Physicians Pilot Projects Pituitary Gland Pituitary Gland Adenoma Pituitary-dependent Cushing&apos s disease Play Precision therapeutics Publishing Peer Reviews Quality of life Radiation therapy Rattus Refractory Repeat Surgery Research Resected Reverse Transcriptase Polymerase Chain Reaction Risk Role Scheme Scientist Somatic Mutation Somatotropin Subgroup Surgeon Testing Time Translating Variant accurate diagnostics base bone cell motility clinically relevant cohort contextual factors disability disorder control epigenome epigenomics experience functional status gene expression variation genome-wide imaging study improved improved outcome insight interest knock-down methylome molecular marker multimodality novel overexpression personalized diagnostics precision drugs prognostic small hairpin RNA supervised learning targeted treatment transcriptome sequencing tumor tumor growth vector

项目摘要

Project Summary: DNA Methylation and gene expression variations influence pituitary adenoma hormonal function and invasive growth Pituitary Adenomas (PAs) are among the most common intracranial tumors, and may cause hypopituitarism, neurological deficits, and lethal hormonal oversecretion disorders such as Cushing's disease and acromegaly. Although typically benign, PA invasion into surrounding dura, bone, and brain is evident in nearly half of symptomatic patients and is the major barrier to achieving long-term tumor control, hormonal remission, and normalized patient survival. Genetic mutations do not play a major role in the development or behavior of non-familial PAs, and a major knowledge gap exists in understanding the molecular underpinnings of PA hormonal function and invasive growth. Alternatively, epigenetic (e.g., DNA methylation) and gene expression alterations are known to influence PA phenotype, but these effects vary with gene location and context. Our team performed the first epigenome-wide pilot study to explore the association of DNA methylation and gene expression with PA behavior, and validated several genes implicated in PA hormonal function and invasion. Using a similar workflow, our overall goal is to define the role that DNA methylation and gene expression play in PA hormonal secretion and invasion in a larger study stratified according to PA hormonal subtype and invasion status. We hypothesize that: 1) variation in DNA methylation and expression is associated with subtype-specific PA hormonal function and invasion; 2) DNA methylation and expression data can be used to identify novel molecularly-defined PA classes and complement current PA diagnostic schemes; and 3) modulated expression of prioritized genes of interest will affect PA hormonal secretion and invasion in vitro. To test these hypotheses, we aim to: 1) use integrative epigenomic profiling and RNA sequencing approaches to analyze surgically-resected invasive and noninvasive PAs derived from a multi-institutional consortium, 2) discover novel molecularly-defined PA subtypes using DNA methylation and gene expression analysis, followed by development of a molecularly-based classification and unified diagnostic scheme, 3) identify candidate DNA methylation and gene expression markers associated with PA hormonal secretion and invasion, 4) use established rat and surgically-resected human PA primary cell lines to test hormonal secretion and invasion phenotypes following modulation of expression of prioritized genes. Understanding the molecular pathways associated with PA hormonal secretion and invasion will provide practitioners with more precise diagnostic information and help to develop targeted drug therapies to curb or reverse PA hormonal oversecretion and invasion, thereby improving patient quality of life and survival. Knowledge derived from this study could help refractory PA patients by helping to mitigate lifelong risks associated with chronic hormone oversecretion, medications, radiation treatment, and repeat surgery.

项目摘要：DNA 甲基化和基因表达变异影响垂体腺瘤荷尔蒙功能和侵袭性生长垂体腺瘤 (PA) 是最常见的颅内肿瘤之一，可能会导致垂体功能减退、神经功能缺陷和致命的激素分泌过多性疾病，例如库欣氏病疾病和肢端肥大症。尽管 PA 通常是良性的，但它会侵入周围的硬脑膜、骨骼和大脑在近一半有症状的患者中很明显，是实现长期肿瘤治疗的主要障碍控制、激素缓解和患者生存正常化。基因突变并不起主要作用在非家族 PA 的发展或行为中的作用，并且在以下方面存在重大知识差距：了解 PA 激素功能和侵袭性生长的分子基础。或者，已知表观遗传（例如 DNA 甲基化）和基因表达改变会影响 PA 表型，但这些影响随基因位置和背景而变化。我们队取得了第一名表观基因组范围内的试点研究探索 DNA 甲基化和基因表达与 PA 行为，并验证了与 PA 激素功能和入侵有关的几个基因。使用类似的工作流程，我们的总体目标是定义 DNA 甲基化和基因表达在一项根据 PA 激素亚型和分层的大型研究中的 PA 激素分泌和侵袭入侵状态。我们假设：1）DNA 甲基化和表达的变化与亚型特异性 PA 激素功能和侵袭； 2) DNA甲基化和表达数据可用于识别新的分子定义的 PA 类别并补充当前的 PA 诊断方案； 3) 感兴趣的优先基因的调节表达将影响 PA 激素的分泌和体外侵袭。为了检验这些假设，我们的目标是：1) 使用综合表观基因组分析和 RNA 测序方法来分析手术切除的侵入性和非侵入性 PA 多机构联盟，2) 使用 DNA 发现新的分子定义的 PA 亚型甲基化和基因表达分析，然后开发基于分子的分类和统一诊断方案，3）识别候选DNA甲基化和基因与 PA 激素分泌和侵袭相关的表达标记，4) 使用已建立的大鼠和手术切除的人 PA 原代细胞系用于测试激素分泌和侵袭表型调节优先基因的表达后。了解分子途径与 PA 激素分泌和侵袭相关的数据将为从业者提供更精确的诊断信息并帮助开发靶向药物疗法来抑制或逆转 PA 激素分泌过多和侵袭，从而提高患者的生活质量和生存率。知识衍生这项研究可以帮助难治性 PA 患者减轻与以下疾病相关的终生风险：慢性激素分泌过多、药物、放射治疗和重复手术。