Identification of human orofacial enhancers and their role in orofacial clefts

人类口面部增强剂的鉴定及其在口面部裂隙中的作用

基本信息

批准号：
9057242
负责人：
Justin Lee Cotney
金额：
$ 24.9万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9057242
关键词：
Address Adult Affect Award Binding Biochemical Biochemistry Biological Assay Birth Branchial arch structure ChIP-seq Chromatin Chromosomes Cleft Lip Code Computing Methodologies Conceptions Congenital Abnormality DNA Data Data Set Defect Development Development Plans Developmental Biology Developmental Gene Disease Elements Embryo Embryonic Development Enhancers Evolution Face FaceBase Faculty Family Functional disorder Future Gene Expression Gene Expression Profile Gene Expression Regulation Gene Targeting Genes Genetic Genetic Markers Genome Goals Graduate Degree Hand Health Heritability Human Human Genetics Human Genome Human Identifications Individual Institution Instruction Jaw Knock-in Mouse Letters Lifting Limb structure Linkage Disequilibrium Live Birth Measures Mentors Methods Mitochondria Molecular Biology Molecular Conformation Mus Mutate Outcome Palate Parents Pathway interactions Patients Pattern Phase Positioning Attribute Postdoctoral Fellow Public Health Publishing Regulator Genes Regulatory Element Research Research Personnel Resources Role Sampling Signal Transduction Single Nucleotide Polymorphism Staging Structure Techniques Testing Therapeutic Tissues Training Transgenic Mice Trust Universities Untranslated RNA Variant Work biobank career development cleft lip and palate cohesin craniofacial embryo tissue falls foot functional genomics genome wide association study genome-wide histone modification human data human disease medical schools member novel orofacial orofacial cleft palatal shelves prevent research study spatiotemporal targeted sequencing transcription factor transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Orofacial clefts are one of the most commonly occurring human birth defects, yet the underlying causes remain largely unknown. Genome wide association studies indicate heritability for such defects, however the vast majority of associations fall outside of genes suggesting defective gene regulation is a major contributor. The proposed work seeks to identify the genetic causes of nonsyndromic cleft lip and palate (NSCLP) by identifying and characterizing gene regulatory sequences that are active in early human orofacial development and disrupted in affected individuals. Preliminary research using functional genomics methods directly in human embryonic tissue has identified thousands of potential orofacial regulatory sequences, including several that are in linkage disequilibrium with single nucleotide polymorphisms strongly associated with NSCLP. This "Pathway to Independence" award application includes a mentored career development plan for transition of the candidate, Dr. Justin Cotney, into an independent investigator, as well an accompanying research plan describing the proposed experiments on identification and characterization of disease-associated variants in gene regulatory sequences. The candidate, Dr. Cotney, is a postdoctoral fellow at Yale University School of Medicine, in the lab of Dr. James Noonan in the Department of Genetics. The work leading to his graduate degree in Genetics and Molecular Biology at Emory University was conducted in the lab of Dr. Gerald Shadel in the Department of Biochemistry at Emory and Department of Genetics at Yale. There he focused on understanding the contributions of two members of a novel class of transcription factors to human mitochondrial gene expression and retrograde signaling. In the Noonan lab, Dr. Cotney applied biochemical and computational methods to identify gene regulatory sequences directly in embryonic limb tissue that have contributed to human-specific evolution of the hand and foot. The techniques and computational methods to address these evolutionary questions in embryonic development can be adapted to understand gene regulation in any developing tissue, placing Dr. Cotney in a unique position to investigate the causes of NSCLP. The mentoring and career development plan detailed within will supplement his background in basic molecular biology and functional genomics with additional training and instruction in statistical genetics and human orofacial development. Dr. Cotney's goal is to become a faculty member in an interdisciplinary bioscience, developmental biology, or similar department at an academic institution, in which he can research the role of dysfunction of developmental gene regulation in common human diseases. The research plan will leverage Dr. Cotney's expertise in functionally profiling embryonic tissue to identify gene regulatory sequences that are active during the formation of pharyngeal arches to fusion of palates and facial structures. The project further proposes to determine which of these activated regulatory elements are burdened with variants and structural changes in NSCLP patients and identify the consequences of disrupted developmental gene regulation. The identification of gene regulatory networks that are commonly perturbed in NSCLP patients will provide genetic markers that can predict the occurrence of these defects and provide targets for future preventative or therapeutic measures. Alleviating the impact of orofacial clefts and preventing their occurrence will increase global public health and lift a large financial burden currently faced by affected individuals and their families.

描述（由申请人提供）：口面部裂是最常见的人类出生缺陷之一，但其根本原因仍然很大程度上未知。全基因组关联研究表明此类缺陷具有遗传性，但绝大多数关联不属于基因范围，表明基因调控缺陷是主要原因。拟议的工作旨在通过识别和表征在人类早期口面部发育中活跃并在受影响个体中被破坏的基因调控序列来确定非综合征性唇腭裂（NSCLP）的遗传原因。直接在人类胚胎组织中使用功能基因组学方法的初步研究已经确定了数千个潜在的口面部调节序列，其中包括一些与单核苷酸多态性与 NSCLP 密切相关。该“独立之路”奖项申请包括一项指导候选人贾斯汀·科特尼博士转变为独立研究者的职业发展计划，以及一项随附的研究计划，描述了在疾病相关变异的识别和表征方面提出的实验。基因调控序列。候选人科特尼博士是耶鲁大学医学院遗传学系詹姆斯·努南博士实验室的博士后研究员。他在埃默里大学获得遗传学和分子生物学研究生学位的工作是在埃默里大学生物化学系和耶鲁大学遗传学系 Gerald Shadel 博士的实验室中进行的。在那里，他专注于了解一类新型转录因子的两个成员对人类线粒体基因表达和逆行信号传导的贡献。在努南实验室，科特尼博士应用生化和计算方法直接识别胚胎肢体组织中的基因调控序列，这些序列有助于人类特有的手和足的进化。解决胚胎发育中这些进化问题的技术和计算方法可以用来了解任何发育组织中的基因调控，使 Cotney 博士处于研究 NSCLP 原因的独特地位。其中详细介绍的指导和职业发展计划将通过统计遗传学和人类口面部发育方面的额外培训和指导来补充他在基础分子生物学和功能基因组学方面的背景。 Cotney 博士的目标是成为跨学科生物科学、发育生物学或学术机构类似部门的教员，他可以在其中研究发育基因调控功能障碍在常见人类疾病中的作用。该研究计划将利用科特尼博士在胚胎组织功能分析方面的专业知识，以确定在咽弓形成到上颚和面部结构融合过程中活跃的基因调控序列。该项目进一步建议确定哪些激活的调控元件受到 NSCLP 患者变异和结构变化的影响，并确定发育基因调控破坏的后果。鉴定 NSCLP 患者中通常受到干扰的基因调控网络将提供可以预测这些缺陷发生的遗传标记，并为未来的预防或治疗措施提供目标。减轻口颌裂的影响并预防其发生将改善全球公共卫生，并减轻受影响个人及其家庭目前面临的巨大经济负担。