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(PQ1) The role of cell-to-cell variation in the penetrance of heritable mutant RAS hypodermal neoplasias

(PQ1) 细胞间变异在可遗传突变 RAS 皮下肿瘤外显率中的作用

基本信息

批准号：
10245157
负责人：
Alexander Richard Mendenhall
金额：
$ 36.85万
依托单位：
UNIVERSITY OF WASHINGTON
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/10245157
关键词：
Affect Alleles Animals Biological Caenorhabditis elegans Cancer-Predisposing Gene Cell Proliferation Cell division Cells Cellular biology Child Clinical Trials Costello syndrome DNA sequencing Data Development Disease Drug Targeting EGF gene Environment Epigenetic Process Event Fluorescence Microscopy Gene Dosage Gene Expression Genes Genetic Genetic Screening Genome Genotype Germ-Line Mutation Goals Heat-Shock Proteins 90 Heritability Homologous Gene Human Image Individual Inherited KRAS2 gene Knowledge Learning Maintenance Malignant Neoplasms Measures Microfluidics Microscopy Modeling Modernization Molecular Molecular Chaperones Mutation Neoplasms Noise Noonan Syndrome Notch and Wnt Signaling Pathway Oncogenes Oncogenic Operating System Organogenesis Output Pathway interactions Patients Penetrance Pharmaceutical Preparations Phenotype Property Proteins RAS genes RNA Interference Reporter Reporter Genes Research Role Scientist Series Severities Signal Transduction Stereotyping System Technology Testing Time Tissues Translations Variant Vulva base biological systems cell transformation deviant experience gain of function gain of function mutation genome editing innovation light microscopy mutant neoplastic novel therapeutics programs ras Oncogene response reverse genetics transcriptome sequencing tumor behavior

项目摘要

Project Summary: Our goal is to provide answers to the question: “What molecular mechanisms influence disease penetrance in individuals who inherit a cancer susceptibility gene?”. We plan to answer this question in terms of genetics and cell biology. More specifically, we plan to identify which genes influence the penetrance of RAS-driven neoplasia, and then observe how these genes alter the stereotyped program of gene expression and cell division by directly observing gene expression and cell division with quantitative light microscopy. Children with Noonan or Costello syndromes are born with mutations in RAS, the most common oncogene. Some, but not all of these individuals develop cancer. RAS-driven cancers are notoriously difficult to treat. Current anti-HSP90 clinical trials show some promise, but the drugs are toxic. We have evidence that other chaperones may be suitable targets for suppressing Ras-based cancer formation. We have evidence that the molecular mechanism that influences Ras-driven neoplasia penetrance is the epigenetically heritable ability to express more or maintain more biologically active molecules of protein per unit gene. In the proposed research, we will study isogenic C. elegans with a Ras gain of function allele that results in incompletely penetrant hypodermal neoplasia. When these animals inherit a gain of function mutation in their sole Ras homolog, let-60, just like children with Noonan syndrome, some of them will develop neoplasias. About 90% of Ras oncogene bearing worms will acquire 1-4 hypodermal neoplasias during development, in response to conserved, cancer- related EGF, Notch and WNT signaling pathways. In worms with wild-type Ras, these pathways would normally control organogenesis of the vulva. The initial manifestation of neoplasia happens reliably, at the same time during development, over and over – right when the signal for vulva development happens. We have a system wherein we know exactly where and when to look, so we can see exactly what happens in cells that may or may not become neoplastic. We will perform a reverse genetic screen to identify genes that affect neoplasia. We will watch how these genes change the series of normally well-coordinated gene expression events that cause cell proliferation and transform cell fate by measuring gene expression while it happens in living cells. Our specific central hypothesis is that animals that do develop neoplasias have epigenetic differences in chaperone expression that cause an increase in translation efficiency, resulting in a higher effective gene dosage of the Ras gain of function allele, and that in turn, results in the manifestation of neoplasia. We provide strong evidence for this hypothesis in the approach.

项目总结：我们的目标是为以下问题提供答案：“什么分子