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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的激素功能和侵袭性生长

基本信息

批准号：
9767099
负责人：
Gabriel Zada
金额：
$ 53.07万
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/9767099
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 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 base bone cell motility clinically relevant cohort contextual factors disability disorder control epigenome epigenomics experience functional status genome-wide imaging study improved improved outcome insight interest knock-down methylome molecular marker multimodality novel overexpression 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.

项目概述：DNA甲基化和基因表达变异对垂体腺瘤的影响