Functional dissection of the regulatory network that governs cardiomyocyte maturation
控制心肌细胞成熟的调节网络的功能剖析
基本信息
- 批准号:10629491
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AdultBirthCRISPR screenCardiacCardiac MyocytesCardiomyopathiesCellsComplexCongenital Heart DefectsDataDefectDepositionDevelopmentDiseaseDisease modelDissectionDown-RegulationEpigenetic ProcessGene ExpressionGene Expression RegulationGenesGeneticGenetic ScreeningGenetic TranscriptionGoalsHeartHeart failureHistone H2BHomeostasisHumanHypertrophic CardiomyopathyHypertrophyIncidenceMapsMentorsMetabolismMolecularMorphologyMusMutateMutationMyosin ATPaseMyosin Heavy ChainsNeonatalOperative Surgical ProceduresPalliative SurgeryPathologicPatientsPhasePhenotypeProcessProductionProtein IsoformsProtocols documentationRegenerative MedicineRegulationRegulatory ElementReplacement TherapyRepressionRoleSarcomeresStressUbiquitinationchromatin modificationconditional knockoutcongenital heart disorderexperimental studyheart functionhemodynamicshistone modificationimprovedin vivoinsightloss of functionmolecular targeted therapiesneonatenovelpromoterregenerative approachresponsesoundtargeted treatmenttooltranscription regulatory network
项目摘要
ABSTRACT
Between birth and adulthood, cardiomyocytes (CMs) undergo profound changes in size, ultrastructure,
metabolism, and gene expression, a process collectively referred to as CM maturation. Although highly
coordinated, the transcriptional network that governs this process is not understood. This lack of understanding
is a barrier to cardiac regenerative medicine, where our current inability to mature CMs differentiated from non-
myocytes limits their use for disease modeling or replacement therapy. In addition, disruption of maturation by
abnormal hemodynamic loads in neonates who have undergone surgery to correct congenital heart defects
likely contributes to their high incidence of heart failure in adulthood. A sound understanding of the regulatory
network governing CM maturation will inspire hypothesis driven attempts to surmount these challenges.
In mice, a key hallmark of CM maturation is sarcomere isoform switching, including the well documented
neonatal switch from Myosin Heavy Chain 7 (Myh7) to Myosin Heavy Chain 6 (Myh6). We have conducted and
validated an in vivo high throughput CRISPR screen for transcriptional regulators of CM maturation, using the
Myh7/6 isoform switch as the readout. Two top candidates from this screen, Rnf20 and Rnf40, form a complex
which governs deposition of the poorly understood chromatin modification histone-2B mono-ubiquitination
(H2Bub1). H2Bub1 function is unexplored in the heart, and associated with congenital heart disease mutations
in human patients. Therefore, In Aim 1 we will perform a detailed characterization of the impact of Rnf20/40 on
genetic regulation of CM maturation.
A major reason why the transcriptional networks controlling CM maturation are poorly understood is
that appropriate tools were previously unavailable. In this proposal we will utilize a suite of novel in vivo tools to
begin mapping the transcriptional regulatory networks that govern CM maturation. In Aim 2 we will seek to
accomplish this goal by dissecting two Myh7 cis-regulatory elements. Furthermore, we will contrast the genetic
regulation of CM maturation with pathological hypertrophy by discovering and describing the key regulatory
mechanisms of Myh7, which is deactivated during maturation and re-activated in response to pathological
stress. These experiments will yield mechanistic clues as to how gene expression is coordinately controlled
during maturation and disease, thus enabling improved CM production protocols and targeted therapies.
Collectively these experiments will begin to map the transcriptional regulatory network that governs maturation
by defining the functions of select trans-acting regulators and cis-regulatory elements.
摘要
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 }}
Nathan James VanDusen其他文献
Nathan James VanDusen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('Nathan James VanDusen', 18)}}的其他基金
Development of tools for rapid systematic refinement of in vivo gene editing technologies
开发用于快速系统完善体内基因编辑技术的工具
- 批准号:
10740025 - 财政年份:2023
- 资助金额:
$ 24.9万 - 项目类别:
Functional dissection of the regulatory network that governs cardiomyocyte maturation
控制心肌细胞成熟的调节网络的功能剖析
- 批准号:
10686262 - 财政年份:2022
- 资助金额:
$ 24.9万 - 项目类别:
Functional dissection of the regulatory network that governs cardiomyocyte maturation.
控制心肌细胞成熟的调节网络的功能剖析。
- 批准号:
9918961 - 财政年份:2019
- 资助金额:
$ 24.9万 - 项目类别:
Functional dissection of the regulatory network that governs cardiomyocyte maturation.
控制心肌细胞成熟的调节网络的功能剖析。
- 批准号:
10348401 - 财政年份:2019
- 资助金额:
$ 24.9万 - 项目类别:
Identification and analysis of factors that regulate cardiomyocyte maturation
心肌细胞成熟调节因素的鉴定与分析
- 批准号:
9379399 - 财政年份:2016
- 资助金额:
$ 24.9万 - 项目类别:
相似海外基金
Cosmic powerhouses: The birth, death, and legacy of black hole jets
宇宙动力源:黑洞喷流的诞生、死亡和遗产
- 批准号:
DP240102970 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
Discovery Projects
Sex-specific fitness landscapes in the evolution of egg-laying vs live-birth
产卵与活产进化中的性别特异性适应性景观
- 批准号:
NE/Y001672/1 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
Research Grant
Sleep and circadian dysfunction in ageing and neurodegeneration: a life course and biomarker study of the British 1946 birth cohort.
衰老和神经退行性疾病中的睡眠和昼夜节律功能障碍:对英国 1946 年出生队列的生命历程和生物标志物研究。
- 批准号:
MR/Y009452/1 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
Fellowship
Giving Hope and minimising trauma when parents are separated from their baby close to birth.
当父母在婴儿即将出生时与婴儿分离时,给予希望并尽量减少创伤。
- 批准号:
ES/Y011112/1 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
Research Grant
MRC National Survey of Health and Development (NSHD, 1946 British Birth Cohort).
MRC 国家健康与发展调查(NSHD,1946 年英国出生队列)。
- 批准号:
MR/Y014022/1 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
Research Grant
‘AIM4SafeBaby®’ (Artificial Intelligence monitoring for Safe baby birth)
–AIM4SafeBaby® –(人工智能监控婴儿安全分娩)
- 批准号:
10065844 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
Collaborative R&D
Critical developmental science: life course trajectories in the 1982 Pelotas birth cohort study
批判发展科学:1982 年佩洛塔斯出生队列研究中的生命历程轨迹
- 批准号:
2341831 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
Continuing Grant
Birth rate and online dating
出生率和网上约会
- 批准号:
24K16364 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The impact of maternal lifestyle and psychosocial factors on neonatal birth weight in Sri Lanka
斯里兰卡母亲生活方式和社会心理因素对新生儿出生体重的影响
- 批准号:
22KF0122 - 财政年份:2023
- 资助金额:
$ 24.9万 - 项目类别:
Grant-in-Aid for JSPS Fellows
The Relationships Between Birth Order, Breastfeeding, and Sleep-Wake Patterns
出生顺序、母乳喂养和睡眠-觉醒模式之间的关系
- 批准号:
480774 - 财政年份:2023
- 资助金额:
$ 24.9万 - 项目类别: