Elucidating the cis-regulatory grammar of human photoreceptors

阐明人类光感受器的顺式调节语法

基本信息

  • 批准号:
    10601005
  • 负责人:
  • 金额:
    $ 53.92万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-04-01 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

Project Summary One of the major unsolved challenges of the genomic era is to understand how individual sequence variation contributes to disease. Coding variation is increasingly well understood, but our knowledge of the effects of non-coding variation remains rudimentary. The goal of this proposal is to develop a platform for the analysis of non-coding cis-regulatory variation in human retinal disease. We hypothesize that sequence variants in photoreceptor-specific cis-regulatory elements (CREs; e.g., enhancer/promoters) play an important role in retinal disease by altering the expression levels of disease-related genes. Currently, assessing the effects of variants that fall within non-coding DNA represents a challenging problem, in part, because our ability to assay CREs in a high-throughput fashion is limited. To address this challenge, we have developed a technique called CRE-seq (Cis-Regulatory Element analysis by sequencing). In CRE-seq, individual CREs are fused to reporter genes, each containing a unique DNA barcode. The resultant CRE-reporter library, consisting of thousands of constructs, is introduced into living retina, and reporter gene expression is quantified by counting barcoded transcripts with RNA-seq. CRE-seq promises to revolutionize our ability to measure the effects of human cis-regulatory variants. To achieve this goal, we propose three Specific Aims. In Aim 1, we will use ATAC-seq to identify candidate CREs in both developing and mature human photoreceptors. In Aim 2, we will utilize a combination of computational and experimental approaches (including CRE-seq analysis) to analyze the CREs identified in Aim 1 and thereby elucidate the cis-regulatory grammar of human photoreceptors. CRE-seq will be performed in both mouse retinas as well as ES cell-derived human retinal organoids. These studies will provide the first comprehensive view of the human photoreceptor 'cis-regulome' and will begin to decipher the cis-regulatory code of human photoreceptors. In Aim 3, we will use a ‘mutagenesis and screening’ approach to engineer a library of compact (150 bp), highly active enhancers for targeting human photoreceptors in gene therapy applications. If successful, these studies will establish a quantitative platform for the analysis of non-coding cis-regulatory variation, thereby enabling comprehensive interpretation of whole-genome sequence data in the context of retinal disease. In addition, they will engineer a suite of new enhancers for human retinal gene therapy.
项目摘要 基因组时代未解决的主要挑战之一是了解个体序列如何 变异导致疾病。编码变异越来越被理解,但是我们对编码变异的了解 非编码变异的影响仍然是基本的。该提案的目标是为 人视网膜疾病中非编码顺式调节变异的分析。我们假设这个序列 光受体特异性顺式调节元件(克雷斯;例如,增强子/启动子)发挥重要作用 通过改变疾病相关基因的表达水平在视网膜疾病中发挥作用。目前,评估 属于非编码DNA的变异的影响代表了一个具有挑战性的问题,部分原因是我们的能力 以高通量方式测定克雷斯是有限的。为了应对这一挑战,我们制定了 CRE-seq(顺式调控元件测序分析)。在CRE-seq中,单独的克雷斯是 与报告基因融合,每个基因含有独特的DNA条形码。得到的CRE-报告基因文库,由以下组成: 将数千种构建体中的一种引入活视网膜中,并通过以下方法定量报告基因表达: 用RNA-seq计数条形码化的转录物。CRE-seq有望彻底改变我们测量 人顺式调节变体的影响。为了实现这一目标,我们提出了三个具体目标。目标1: 将使用ATAC-seq来鉴定发育和成熟人类光感受器中的候选克雷斯。在目标2中, 我们将利用计算和实验方法(包括CRE-seq分析)的组合, 分析目标1中鉴定的克雷斯,从而阐明人类的顺式调节语法。 光感受器CRE-seq将在小鼠视网膜以及ES细胞衍生的人视网膜细胞中进行。 类器官这些研究将提供人类光感受器顺式调节组的第一个全面视图 并将开始破译人类光感受器的顺式调节密码。在目标3中,我们将使用 “诱变和筛选”方法来工程化紧凑(150 bp)的高活性增强子文库, 在基因治疗应用中靶向人类光感受器。如果成功,这些研究将建立一个 用于分析非编码顺式调控变异的定量平台,从而实现全面的 在视网膜疾病的背景下全基因组序列数据的解释。此外,他们还将设计一个 一套用于人视网膜基因治疗新增强子。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Partitioning of gene expression among zebrafish photoreceptor subtypes.
  • DOI:
    10.1038/s41598-021-96837-z
  • 发表时间:
    2021-08-30
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    Ogawa Y;Corbo JC
  • 通讯作者:
    Corbo JC
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

JOSEPH CORBO其他文献

JOSEPH CORBO的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('JOSEPH CORBO', 18)}}的其他基金

Targeting Nr2e3 to prevent photoreceptor degeneration
靶向 Nr2e3 预防光感受器变性
  • 批准号:
    10587113
  • 财政年份:
    2023
  • 资助金额:
    $ 53.92万
  • 项目类别:
High-throughput identification of causal variants underlying neuropsychiatric disease-related GWAS hits
高通量鉴定神经精神疾病相关 GWAS 命中的因果变异
  • 批准号:
    10339452
  • 财政年份:
    2020
  • 资助金额:
    $ 53.92万
  • 项目类别:
High-throughput identification of causal variants underlying cardiac arrhythmia-related GWAS hits
高通量识别心律失常相关 GWAS 命中的因果变异
  • 批准号:
    10615090
  • 财政年份:
    2020
  • 资助金额:
    $ 53.92万
  • 项目类别:
High-throughput identification of causal variants underlying cardiac arrhythmia-related GWAS hits
高通量识别心律失常相关 GWAS 命中的因果变异
  • 批准号:
    10397430
  • 财政年份:
    2020
  • 资助金额:
    $ 53.92万
  • 项目类别:
High-throughput identification of causal variants underlying neuropsychiatric disease-related GWAS hits
高通量鉴定神经精神疾病相关 GWAS 命中的因果变异
  • 批准号:
    10569114
  • 财政年份:
    2020
  • 资助金额:
    $ 53.92万
  • 项目类别:
High-throughput identification of causal variants underlying cardiac arrhythmia-related GWAS hits
高通量识别心律失常相关 GWAS 命中的因果变异
  • 批准号:
    10191029
  • 财政年份:
    2020
  • 资助金额:
    $ 53.92万
  • 项目类别:
Elucidating the cis-regulatory grammar of human photoreceptors
阐明人类光感受器的顺式调节语法
  • 批准号:
    10372052
  • 财政年份:
    2020
  • 资助金额:
    $ 53.92万
  • 项目类别:
DECIPHERING THE MECHANISTIC BASIS OF INFRARED VISION FOR OPTOGENETIC APPLICATIONS
破译红外视觉光遗传学应用的机制基础
  • 批准号:
    9082683
  • 财政年份:
    2016
  • 资助金额:
    $ 53.92万
  • 项目类别:
DISSECTING THE CIS-REGULATORY ARCHITECTURE OF THE RETINA BY EPIGENOMIC PROFILING
通过表观基因组分析剖析视网膜的 CIS 调控架构
  • 批准号:
    9043099
  • 财政年份:
    2015
  • 资助金额:
    $ 53.92万
  • 项目类别:
CONVERTING BIPOLAR CELLS INTO RED-SHIFTED OPTOGENETIC SENSORS FOR RETINAL THERAPY
将双极细胞转化为红移光遗传学传感器用于视网膜治疗
  • 批准号:
    8989104
  • 财政年份:
    2015
  • 资助金额:
    $ 53.92万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 53.92万
  • 项目类别:
    Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 53.92万
  • 项目类别:
    Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 53.92万
  • 项目类别:
    Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 53.92万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 53.92万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 53.92万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 53.92万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 53.92万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 53.92万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 53.92万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了