Human-specific gene changes in cranial sutures

颅缝中人类特异性基因变化

• 批准号: 9287783
• 负责人: Craig Barrett Lowe
• 金额: $ 13.28万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-16 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9287783
• 关键词: Affect; American; Anatomy; Animal Model; Antidepressive Agents; Area; Automobile Driving; Award; Awareness; Biological Assay; Biological Models; Brain; Cells; Cephalic; Congenital abnormal Synostosis; Craniosynostosis; DNA; Data; Dental; Development; Developmental Biology; Disease; Disease susceptibility; Distant; Dura Mater; Engineering; Enhancers; Event; Exposure to; Funding; Genes; Genetic; Genomics; Goals; Growth; Head; Health; Histology; Human; Human Biology; Interdisciplinary Study; International; Jaw; Joint structure of suture of skull; Knockout Mice; Knowledge; Lead; Left; Link; Literature; Malocclusion; Mammalian Genetics; Mentors; Modeling; Molecular; Molecular Biology; Morphology; Mus; Mutation; Myopathy; Nucleic Acid Regulatory Sequences; Osteoblasts; Osteogenesis; Pattern; Phenotype; Physicians; Physiological; Pongidae; Predisposition; Pregnancy; Public Health; Regulatory Element; Reporting; Research; Research Activity; Research Infrastructure; Research Personnel; Research Project Grants; Risk; Rodent; Selective Serotonin Reuptake Inhibitor; Serotonergic System; Serotonin; Signal Transduction; Skeletal Development; Structure; Surgical sutures; Surveys; System; Temporomandibular Joint Disorders; Testing; Time; Tissues; Training; Training Activity; Transgenic Organisms; Universities; Woman; Work; Writing; X-Ray Computed Tomography; base; bone; career; career development; computer science; craniofacial; craniofacial development; cranium; density; experimental study; fetal; human disease; improved; innovation; insight; meetings; novel; novel strategies; postnatal; premature; prenatal; professor; public health relevance; receptor; research and development; research study; serotonin receptor; skull abnormality; trait; translational impact; translational medicine

 DESCRIPTION (provided by applicant): This award will both fund research to identify genomic mutations that have made humans uniquely susceptible to certain craniofacial disorders, as well as provide training and career development for Dr. Lowe to apply his quantitative background to research focusing on human health and disease. Mice have long been the favored system for mammalian genetics and development. Mice and humans share many fundamental features of mammalian development, making it possible to model many aspects of human health and disease using the mouse system. However, there are anatomical and physiological specializations in both species. For example, humans have a different dental pattern than rodents. Even compared to other great apes, humans have reduced jaws and greatly enlarged cranial capacity. The very traits that underlie human biology may also increase susceptibility to particular diseases, such as craniosynostosis and skull abnormalities, dental impaction, malocclusions, and temporomandibular joint and muscle disorders. It is now possible to begin understanding the molecular basis of human specific traits and disease susceptibilities, by combining large scale surveys of human specific DNA changes, with functional data on regulatory elements, flanking genes, and phenotypic effects in model systems. Multiple research studies have reported links between the serotonin system and skull development in humans, a link that has not been seen in mice. Dr. Lowe presents preliminary data showing that humans have a transposon insertion that upregulates expression of the serotonin receptor HTR1B in developing sutures, a molecular change likely to contribute to both delayed suture closure and sensitivity to serotonin signaling during skull development. During the award Dr. Lowe will: (1) identify the cells and tissues affected by the human specific enhancer, (2) recreate the human specific regulatory change and identify the phenotypes that result from similar expression of HTR1B in sutures of mice, (3) expand beyond this example to test whether similar lineage specific regulatory changes have reshaped other unique features of human craniofacial development. The results from this work are expected to have a positive impact on translational medicine by making physicians aware of the molecular mechanisms linking the serotonin system and skull development, and possibly suggesting new strategies for promoting suture patency when synostosis is detected early. This work will be conducted in the Developmental Biology Department at Stanford University and mentored by Professor David Kingsley, an expert in vertebrate genetics and skeletal development with an outstanding track record of preparing trainees for independent careers. Stanford University has extensive research infrastructure to support the proposed research. Dr. Lowe will receive formal training in histology, craniofacial development, and the use of xray computed tomography to quantify bone morphology, volume, and density. He will attend multiple Stanford, Bay Area, and international meetings in skeletal and craniofacial development, to provide broad exposure to problems and approaches in the field. Dr. Lowe will also be mentored by experts in molecular biology, genetics, and developmental biology to augment his background in computer science and immerse him in research projects related to human health and disease. Extensive practice in both speaking and writing will accompany the planned experimental work. The combination of research and training activities will prepare Dr. Lowe to become an independent investigator, managing his own interdisciplinary research lab. Dr. Lowe's unique background will bring innovative new approaches to the field, and should lead to important new insights into both the genomic and genetic basis of human craniofacial traits and disease susceptibilities that are unique to humans.

 描述(由申请者提供)：该奖项将资助研究，以确定使人类对某些头面部疾病特别敏感的基因组突变，并为洛博士提供培训和职业发展，以便将他的量化背景应用于专注于人类健康和疾病的研究。长期以来，小鼠一直是哺乳动物遗传和发育的首选系统。小鼠和人类有许多哺乳动物发育的基本特征，这使得使用小鼠系统对人类健康和疾病的许多方面进行建模成为可能。然而，这两个物种在解剖学和生理学上都有各自的特点。例如，人类的牙齿模式与啮齿动物不同。即使与其他类人猿相比，人类的颌骨也缩小了，颅骨的容量也大大增加了。人类生物学基础的特征也可能增加对特定疾病的易感性，如颅缝闭锁和头骨异常、牙齿阻生、错牙合以及颞下颌关节和肌肉疾病。现在，通过结合对人类特定DNA变化的大规模调查，与模型系统中调节元件、侧翼基因和表型效应的功能数据相结合，现在可以开始了解人类特定特征和疾病易感性的分子基础。多项研究报告了5-羟色胺系统与人类头骨发育之间的联系，这种联系在老鼠身上还没有见过。洛博士提供的初步数据显示，人类有一个转座子插入，可以上调5-羟色胺受体HTR1B在发育缝合中的表达，这种分子变化可能会导致缝合延迟，并在颅骨发育过程中对5-羟色胺信号敏感。在获奖期间，Lowe博士将：(1)确定受人类特有增强子影响的细胞和组织，(2)重建人类特有的调控变化，并确定由于HTR1B在小鼠的缝合线中相似表达而导致的表型，(3)扩展到本示例之外，以测试类似的谱系特定调控变化是否重塑了人类颅面发育的其他独特特征。这项工作的结果有望对转化医学产生积极影响，使医生意识到5-羟色胺系统和头骨发育之间的分子机制，并可能提出新的策略，在早期发现融合时促进缝合开放。这项工作将在斯坦福大学发育生物学系进行，由脊椎动物遗传学和骨骼发育专家大卫·金斯利教授指导，他在培训学员为独立职业做准备方面有着出色的记录。斯坦福大学拥有广泛的研究基础设施来支持拟议的研究。Lowe博士将接受组织学、颅面发育以及使用x射线计算机断层扫描来量化骨骼形态、体积和密度方面的正式培训。他将出席斯坦福大学、湾区和多个骨骼和颅面发育国际会议，以提供对该领域问题和方法的广泛接触。洛威博士还将接受分子生物学、遗传学和发育生物学专家的指导，以增强他在计算机科学方面的背景，并让他沉浸在与人类健康和疾病有关的研究项目中。计划中的实验工作将伴随着广泛的口语和写作练习。研究和培训活动的结合将使洛博士做好准备，成为一名独立的研究员，管理自己的跨学科研究实验室。洛博士独特的背景将为这一领域带来创新的新方法，并将导致对人类独有的头面部特征和疾病易感性的基因组和遗传基础的重要新见解。