Mechanisms of developmental buffering

发育缓冲机制

• 批准号: 10380060
• 负责人: James Tucker Nichols
• 金额: $ 45.15万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10380060
• 关键词: Address; Adult; Affect; Animals; Breeding; Buffers; Cells; Counseling; Craniofacial Abnormalities; DNA; DNA Sequence; DNA Sequence Alteration; Defect; Dental; Development; Developmental Process; Disease; Disease Management; Dorsal; Epigenetic Process; Equilibrium; Fingers; Fishes; Future; Gene Expression; Gene Expression Regulation; Gene Family; Genes; Genetic; Genetic Diseases; Genetic Variation; Genotype; Head; Health; Heritability; Human; Human Genetics; Human Genome; Individual; Inherited; Label; Lead; Measurement; Measures; Medical; Methods; Mission; Modeling; Mutation; National Institute of Dental and Craniofacial Research; Oral; Organism; Orthologous Gene; Pathway interactions; Penetrance; Phenotype; Reporting; Research; Signal Transduction; Skeleton; Specific qualifier value; Statistical Data Interpretation; Symptoms; System; Testing; Tissues; Variant; Work; Zebrafish; craniofacial; design; disease diagnosis; disease phenotype; disorder prevention; epigenome; epigenomics; experimental study; falls; flexibility; gene interaction; genetic manipulation; genetic predictors; genetic variant; genome editing; genome sequencing; improved; member; mutant; notch protein; novel therapeutic intervention; response; screening; skeletal; transcription factor; transcriptomics; zebrafish genome

PROJECT SUMMARY/ABSTRACT: The long-term objective of this proposal is to understand genetic buffering, or how some individuals overcome the effects of a harmful genetic mutation. We generated a zebrafish model of buffering in order to understand how individuals who should have gotten sick are somehow able to live unaffected healthy lives. In our model, we used selective breeding to generate two strains of zebrafish that develop dramatically different head skeletons in response to the same harmful genetic mutation. In one strain, the mutation causes severe, lethal skeletal defects. Meanwhile, the other strain is remarkably buffered against the mutation. The buffered fish develop essentially normal head skeletons, surviving to be fertile, viable adults. We compare these strains to understand the natural buffering mechanisms that are present in some fish, and likely in some humans too. We hypothesize that buffering is due to factors that tune developmental processes to restore balance. For example, in Aim1 we will determine how DNA sequences which oppose the mutant gene can be turned down. In Aim 2 we examine how factors encoded in the DNA which perform the same function as the mutant gene can be turned up. In Aim 3 we will determine how changes that do not necessarily involve alterations in the DNA sequence can buffer the harmful mutation. These three specific aims test how interacting mechanisms function together to buffer development. We designed experiments to address these aims using state of the art methods like genome editing and sequencing, colorful cell and tissue labeling, quantitative measurements of large numbers of fish skeletons, and rigorous statistical analyses. The mechanisms we propose to study here are present in many developmental systems and organisms and therefore will likely be applicable in wide- ranging settings. This study of buffering mechanisms could lead to novel therapeutic approaches, buffering mechanisms might be manipulated in the future to manage disease symptoms. This work will also lead to a better understanding of the factors that make predicting genetic disease from gene sequences difficult. Thus, this line of research will potentially inform and improve medical practices, including genetic disease management, disease diagnosis, and counseling, falling squarely within the mission of the NIDCR to improve dental, oral and craniofacial health through research.

项目摘要/摘要： 该提议的长期目标是了解遗传缓冲，或者某些人如何克服 有害基因突变的影响。我们生成了一种斑马鱼模型，以了解 应该如何生病的个人能够以某种方式过着不受影响的健康生活。在我们的模型中 我们使用选择性育种来产生两种斑马鱼菌株，这些斑马会形成截然不同的头部 骨骼响应相同的有害基因突变。在一个菌株中，突变会导致严重的致命 骨骼缺陷。同时，另一个菌株在突变中被明显缓冲。缓冲鱼 发展基本正常的头部骨骼，幸存下来是肥沃的，可行的成年人。我们将这些压力与 了解某些鱼类中存在的自然缓冲机制，也可能在某些人类中。我们 假设缓冲是由于调整发育过程以恢复平衡的因素所致。为了 例如，在AIM1中，我们将确定如何拒绝反对突变基因的DNA序列。 在AIM 2中，我们研究了在DNA中编码与突变基因相同功能的因素如何 可以升起。在AIM 3中，我们将确定不一定涉及更改的变化如何 DNA序列可以缓冲有害突变。这三个特定目的测试了如何相互作用的机制 合作起到缓冲区开发。我们设计了实验，以使用最新的状态来解决这些目标 基因组编辑和测序，彩色细胞和组织标记等方法，定量测量 大量鱼类骨骼和严格的统计分析。我们建议在这里研究的机制 存在于许多发育系统和生物中，因此可能适用于广泛的 设置。这项对缓冲机制的研究可能导致新型治疗方法，缓冲 将来可能会操纵机制来管理疾病症状。这项工作也将导致 更好地了解使基因序列预测遗传疾病的因素。因此， 这项研究将有可能为医学实践提供信息，包括遗传疾病 管理，疾病诊断和咨询，直接落在NIDCR的任务之内 通过研究牙齿，口腔和颅面健康。