Critical Sorting Steps and Pathways in the Trafficking of Cardiac Sarcoplasmic Reticulum Proteins
心脏肌浆网蛋白运输的关键分选步骤和途径
基本信息
- 批准号:10719667
- 负责人:
- 金额:$ 66.51万
- 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:2023-06-15 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:Adrenergic AgentsAdultAnabolismAnimal ModelBindingBiochemicalCardiacCardiac MyocytesCarrier ProteinsCell membraneCellsChronicCommunicationComplexCytoplasmDataDedicationsDiseaseDistalEndoplasmic ReticulumFailureFunctional disorderGolgi ApparatusGrowthHeartHeart DiseasesHeart HypertrophyHeart failureHypertrophyImmunologicsImmunology procedureIntercalated discKnowledgeLeadLocationMembraneMembrane ProteinsMessenger RNAMicrotubulesMolecularMorphologyMotorMuscle CellsNuclearNuclear EnvelopeNuclear PoreOrgan failurePathway interactionsPeptide Signal SequencesPhysiologicalPreparationProcessProtein BiosynthesisProtein SortingsProteinsProteomeProteomicsPumpRadialRegulationRibosomesRough endoplasmic reticulumRyanodine Receptor Calcium Release ChannelSERCA2aSarcolemmaSarcomeresSarcoplasmic ReticulumSiteSortingSubcellular structureSymptomsSystemTertiary Protein StructureTestingTherapeuticTherapeutic InterventionTranslatingTranslationsTransmembrane DomainTubular formationdesignguided inquirymRNA Translationnew therapeutic targetnovelnovel therapeuticsphospholambanphospholemmanprotein distributionprotein transportresponserough endoplasmic reticulum cisternasextargeted treatmenttherapeutic targettherapeutically effectivetraffickinguptake
项目摘要
Cardiac hypertrophy can lead to heart failure, with few treatment options. Hypertrophic growth inevitably
requires mechanisms of protein distribution, as studies show the involvement of both increased mRNA
translation and mRNA trafficking along microtubules. Yet, how the distribution of membrane proteins occurs and
responds to hypertrophic growth is unknown. While sarcoplasmic reticulum (SR) Ca handling is key to
hypertrophy, we do not know how trafficking of SR proteins occurs using cardiomyocyte specific mechanisms,
nor its regulation and response to hypertrophy, which precludes discovery of key targets for therapeutics. To
probe this mechanism and identify sites of regulation, we have focused on a common portion of the biosynthetic
membrane pathway where the rough endoplasmic reticulum (ER) organizes and sorts proteins for transit into
SR tubules. Using a species-specific expression and immunological analysis to study the early steps of SR
protein trafficking in adult cardiomyocytes, we show that newly synthesized proteins first accumulate into
organized perinuclear ER puncta aligned with z-lines, and then transit to transverse SR z-tubules that aligned
with T-tubules. Such morphology is observed for all newly made proteins examined, except for phospholamban,
suggesting commonality of these protein sorting sites in ER. Afterward, motors can power transport of proteins
both radially and axially via microtubules to their steady state distributions. These data lead to our hypotheses
that newly synthesized SR proteins are sorted in a specific set of perinuclear ER subdomains, which are
organized by the alignment with z-lines and in proximity to nuclear pores and translocons, contain critical ER
trafficking proteins, and allow newly made SR proteins to develop their initial functional interactions for transit to
SR. Such cellular sorting and trafficking steps adapt to the physiological demands, but maladapt to hypertrophic
heart failure, which are likely amenable to develop new therapeutics regulating membrane protein trafficking. To
dissect biochemical features of these sorting sites and trafficking steps, we have developed key experimental
systems to determine progressive protein distribution 12-48 h after translation of three small single
transmembrane domain proteins that are destined to different subcellular locations. Included is phospholamban
(in the nuclear envelope and in longitudinal SR for Ca uptake), junctin (in junctional SR for Ca release), and
phospholemman (in sarcolemma and intercalated discs to regulate the Na, K-pump). Aim 1 will determine: if a
single perinuclear ER subdomain can effectively accumulate and co-localize newly made SR proteins (junctin
and phospholamban), but separate phospholemman, for their diverse and distinct steady state distributions; if
sites are aligned with nuclear pores, translocons; and if known ER trafficking proteins, newly identified in our
SERCA-activated SR proteome, will modulate these trafficking steps. Aim 2 will determine whether a
hypertrophic response modulates the accumulations of protein into any of the ER sorting sites, their common
biosynthesis pathways, or the novel sets of cardiac ER trafficking proteins, in animal models of hypertrophy.
心脏肥厚可导致心力衰竭,治疗选择很少。肥厚生长不可避免
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 }}
Zhenhui Chen其他文献
Zhenhui Chen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 }}
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 66.51万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 66.51万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 66.51万 - 项目类别:
Standard Grant
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 66.51万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 66.51万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 66.51万 - 项目类别:
Discovery Early Career Researcher Award
Laboratory testing and development of a new adult ankle splint
新型成人踝关节夹板的实验室测试和开发
- 批准号:
10065645 - 财政年份:2023
- 资助金额:
$ 66.51万 - 项目类别:
Collaborative R&D
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 66.51万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 66.51万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 66.51万 - 项目类别:
Grant-in-Aid for Scientific Research (C)