Developmental and genetic function of SHROOM3
SHROOM3的发育和遗传功能
基本信息
- 批准号:10587298
- 负责人:
- 金额:$ 53.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-01 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:ActomyosinAddressAnimal ModelApicalBindingBiological AssayCause of DeathCell LineageCell PolarityCellsChildCongenital AbnormalityCongenital Heart DefectsCytoskeletonDataDefectDevelopmentDevelopmental BiologyDisease susceptibilityEmbryonic HeartEtiologyExhibitsFamilyFrequenciesGenesGeneticGenetic EpistasisGenetic Predisposition to DiseaseGenomicsHeart AbnormalitiesHeterozygoteHumanHuman GeneticsImmunoprecipitationIn VitroIndianaInvestigationKnowledgeLeadLinkMass Spectrum AnalysisMovementMusMutateMutationOutcomePathway interactionsPatientsPediatric Cardiac Genomics ConsortiumPenetrancePhenocopyPhenotypePredispositionPrognosisProteinsRho-associated kinaseRoleShapesSignal PathwaySignal TransductionTechnologyTestingTissuesTranslatingVariantVentricular Septal DefectsXenopusbiobankcardiogenesiscell motilitycohortcongenital heart disorderconstrictiondevelopmental geneticsdisease phenotypeexomeexome sequencingfunctional genomicsgenetic architecturegenetic testinggenetic variantgenome sequencinggenome wide association studyhuman diseasehuman genomicshuman modelimprovedin vivomembermouse modelnovelplanar cell polarityprotein protein interactionpublic health relevancerare variantrisk predictionsingle-cell RNA sequencingtranscriptome sequencingwhole genome
项目摘要
PROJECT SUMMARY
Congenital heart disease (CHD) is the most common cause of death due to birth defects. Despite its frequency,
identifying genetic causes of CHD has been challenging. Mendelian inheritance of sporadic (nonsyndromic) CHD
is rare. Instead, the genetic architecture of CHD is characterized by non-penetrance, variable expressivity, and
likely oligogenic effects. Although genome wide association studies, trio, and family-based studies have been
utilized, there has been little emphasis on examining epistasis, additive effects, or mutational burden.
Furthermore, although an improved understanding of cardiac development has identified genes and pathways
that underlie CHD in animal models, this knowledge has not always translated readily into an understanding of
disease causation in human CHD. In order to improve our ability to predict risk for CHD and prognosis, it is
important to identify new genes and pathways that contribute to sporadic CHD and integrate functional genomics
for variant analysis with developmental biology for mechanistic understanding. We propose to address these
critical needs through investigation of a novel gene causing cardiac malformations, SHROOM3, and delineation
of its interactome, as an exemplar leveraging human genomics and developmental biology. The aims of this
study are to: 1) test the hypothesis that cardiogenesis requires SHROOM3 interaction with planar cell polarity
(PCP) proteins and downstream effectors. The outcome of this aim will identify cell- and tissue-specific
consequences of loss of Shroom3, identify its interactome and consequence of its genetic interactions on CHD;
and 2) test the hypothesis that rare variants in genes encoding PCP signaling and downstream effector proteins
are enriched in patients with CHD. The outcome of this aim will functionally validate SHROOM3 rare variants
and identify genes and pathways important for the susceptibility to CHD. Using a combination of functional
genomics to define the impact of rare variants, mechanistic studies using mouse models, and human genetics,
these studies will collectively define the role of SHROOM3 in heart development and the contribution of
SHROOM3 and PCP pathway members to the genetic architecture of CHD.
项目摘要
先天性心脏病(CHD)是由于出生缺陷导致死亡的最常见原因。尽管它的频率,
确定冠心病的遗传原因一直是一个挑战。散发性(非综合征性)CHD的孟德尔遗传
是罕见的。相反,CHD的遗传结构的特点是非特异性,可变的表达性,
可能是寡基因效应。尽管全基因组关联研究、三人组研究和基于家族的研究已经进行
利用,很少强调检查上位性,加性效应,或突变负担。
此外,尽管对心脏发育的进一步了解已经确定了基因和途径,
在动物模型中,这些知识并不总是容易转化为对冠心病的理解,
人类CHD的病因。为了提高我们预测冠心病风险和预后的能力,
重要的是要确定新的基因和途径,有助于散发性冠心病和整合功能基因组学
用发育生物学进行变异分析,以了解机制。我们建议解决这些问题
通过研究引起心脏畸形的新基因SHROOM 3和描绘的关键需求
作为利用人类基因组学和发育生物学的典范。其目的是
研究是:1)测试心脏发生需要SHROOM 3与平面细胞极性相互作用的假设
(PCP)蛋白质和下游效应物。这一目标的结果将确定细胞和组织特异性
Shroom 3缺失的后果,鉴定其相互作用组及其对CHD的遗传相互作用的后果;
和2)测试编码PCP信号传导和下游效应蛋白的基因中的罕见变体
在冠心病患者中富集。这一目标的结果将在功能上验证SHROOM 3罕见变体
并确定对冠心病易感性重要的基因和途径。使用函数的组合
基因组学,以确定罕见变异的影响,使用小鼠模型的机制研究,和人类遗传学,
这些研究将共同确定SHROOM 3在心脏发育中的作用,
SHROOM 3和PCP通路成员与CHD的遗传结构
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
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 }}
Stephanie M Ware其他文献
Genetics of human heterotaxias
人类内脏异位的遗传学
- DOI:
10.1038/sj.ejhg.5201506 - 发表时间:
2005-10-26 - 期刊:
- 影响因子:4.600
- 作者:
Lirong Zhu;John W Belmont;Stephanie M Ware - 通讯作者:
Stephanie M Ware
4 – Adults With Congenital Heart Disease: A Genetic Perspective
4 – 患有先天性心脏病的成年人:遗传学视角
- DOI:
- 发表时间:
2017 - 期刊:
- 影响因子:0
- 作者:
W. A. Kay;Stephanie M Ware - 通讯作者:
Stephanie M Ware
Approaches to Studying Outcomes in Patients With Congenital Heart Disease With Genetic Syndromes: What Down Syndrome Can Teach Us
研究患有遗传综合症的先天性心脏病患者的结果的方法:唐氏综合症可以教会我们什么
- DOI:
10.1161/jaha.123.033193 - 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Stephanie M Ware - 通讯作者:
Stephanie M Ware
1114-202 Effects of beta-adrenergic blockade in pediatric marfan syndrome
- DOI:
10.1016/s0735-1097(04)91635-x - 发表时间:
2004-03-03 - 期刊:
- 影响因子:
- 作者:
Karina M Carlson;Pamela E Ganz;E.O Smith;William Craigen;Stephanie M Ware;Susan Fernbach;John W Belmont;Steven R Neish;Jeffrey A Towbin - 通讯作者:
Jeffrey A Towbin
Stephanie M Ware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('Stephanie M Ware', 18)}}的其他基金
Left-right patterning abnormalities and cardiac morphogenesis
左右模式异常和心脏形态发生
- 批准号:
9208534 - 财政年份:2017
- 资助金额:
$ 53.09万 - 项目类别:
The role of ZIC3 within cardiomyocyte precursors in cardiac morphogenesis
ZIC3 在心肌细胞前体细胞中在心脏形态发生中的作用
- 批准号:
10495949 - 财政年份:2017
- 资助金额:
$ 53.09万 - 项目类别:
Role of the Embryonic Node in Cardiac Development and Congenital Heart Disease
胚胎节点在心脏发育和先天性心脏病中的作用
- 批准号:
7837549 - 财政年份:2009
- 资助金额:
$ 53.09万 - 项目类别:
Role of the Embryonic Node in Cardiac Development and Congenital Heart Disease
胚胎节点在心脏发育和先天性心脏病中的作用
- 批准号:
7588010 - 财政年份:2007
- 资助金额:
$ 53.09万 - 项目类别:
Role of the Embryonic Node in Cardiac Development and Congenital Heart Disease
胚胎节点在心脏发育和先天性心脏病中的作用
- 批准号:
8056809 - 财政年份:2007
- 资助金额:
$ 53.09万 - 项目类别:
Role of the Embryonic Node in Cardiac Development and Congenital Heart Disease
胚胎节点在心脏发育和先天性心脏病中的作用
- 批准号:
7386696 - 财政年份:2007
- 资助金额:
$ 53.09万 - 项目类别:
Role of the Embryonic Node in Cardiac Development and Congenital Heart Disease
胚胎节点在心脏发育和先天性心脏病中的作用
- 批准号:
7781379 - 财政年份:2007
- 资助金额:
$ 53.09万 - 项目类别:
Role of the Embryonic Node in Cardiac Development and Congenital Heart Disease
胚胎节点在心脏发育和先天性心脏病中的作用
- 批准号:
7249754 - 财政年份:2007
- 资助金额:
$ 53.09万 - 项目类别:
Zic3 and the Control of Body Pattern Formation
Zic3 和身体模式形成的控制
- 批准号:
6322902 - 财政年份:2001
- 资助金额:
$ 53.09万 - 项目类别:
Zic3 and the Control of Body Pattern Formation
Zic3 和身体模式形成的控制
- 批准号:
6642116 - 财政年份:2001
- 资助金额:
$ 53.09万 - 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:
$ 53.09万 - 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:
$ 53.09万 - 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:
$ 53.09万 - 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:
$ 53.09万 - 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:
$ 53.09万 - 项目类别:
Standard Grant
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:
$ 53.09万 - 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:
$ 53.09万 - 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:
$ 53.09万 - 项目类别:
EU-Funded
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:
$ 53.09万 - 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:
$ 53.09万 - 项目类别:
Research Grant