Zinc is a Novel Ligand of Nuclear Receptors
锌是核受体的新型配体
基本信息
- 批准号:9760108
- 负责人:
- 金额:$ 2.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:Acidic Amino AcidsAddressAffectAffinityAnimal ModelAnimalsBindingBiological AssayBiological ModelsBiological ProcessBiologyCaenorhabditis elegansCell Culture TechniquesCell NucleusCellsCommunitiesCysteineDNADNA Binding DomainDevelopmentDietDietary ZincDiseaseElementsEnhancersEquilibriumExcretory functionFUS-1 ProteinGenesGenetic TranscriptionGoalsHealthHistidineHomeostasisHomology ModelingHumanHuman BiologyHypersensitivityIn VitroLaboratoriesLeadLifeLigand Binding DomainLigandsMediatingMedical ResearchMetabolismMetalsMethodsModelingMutateNematodaNuclear Orphan ReceptorNuclear ReceptorsNutrientOrphanOrthologous GenePathologyPhenotypePlanet EarthPlayProcessProteinsReagentRegulationRoleSignal Transduction PathwaySpecificityStructureSystemTestingToxic effectTransgenic OrganismsZincZinc deficiencybasebiological systemsexperimental studygenetic manipulationhuman diseasein vivoinnovationmutantnovelnovel therapeutic interventionreceptorreceptor functionresponsesensortraffickingtranscription factoruptakezinc-binding protein
项目摘要
Zinc is an essential human nutrient that must be tightly regulated, as both zinc excess and deficiency are
deleterious. Sophisticated mechanisms of zinc homeostasis allow animals to sense and respond to imbalances
in zinc at the cellular level. However, the understanding of these mechanisms remains incomplete. Our recent
discoveries in the roundworm C. elegans have suggested new models for mechanisms of zinc homeostasis
that have important implications for human biology. C. elegans has proven to be an ideal model organism for
the study of zinc biology thanks to new methods in manipulating dietary zinc in media, newly described metal-
related phenotypes, and genetic manipulations common in the worm community. In this system, we discovered
that the High Zinc Activation (HZA) element mediates the transcriptional response of multiple genes in
response to high dietary zinc. Further, we discovered the high zinc activated nuclear receptor (HIZR-1), which
is the master regulator of zinc homeostasis, as hizr-1(lf) mutants fail to induce zinc response genes and these
mutants are hypersensitive to zinc toxicity. The HIZR-1 DNA binding domain (DBD) directly binds the HZA and
the HIZR-1 ligand-binding domain (LBD) directly binds zinc. HIZR-1 responds to high dietary zinc by
accumulating in the nucleus. Most interestingly, a chimeric Gal4(DBD)::HIZR-1(LBD) fusion protein confers
zinc responsiveness in human cell culture. These observations suggested two exciting hypotheses: (1) HIZR-1
responds to high levels of zinc because specific cysteine, histidine and/or acidic amino acids in the ligand-
binding domain directly coordinate zinc. (2) The high zinc homeostasis response in human cells is regulated by
a functional human ortholog of hizr-1. I will test these hypotheses by, (1) defining the mechanism of zinc
binding by structure-function analysis of the HIZR-1 ligand binding domain, and, (2) determining if a human
orphan nuclear receptor senses high zinc by directly binding zinc in vitro and in vivo. These studies will be
impactful by defining the mechanism of action of a new high zinc sensor and potentially identifying a human
high zinc sensor with implications for treating human diseases of abnormal zinc homeostasis. The ability of
animals to sense high and low dietary zinc and respond by adjusting uptake, storage and excretion is critical
for homeostasis. The proposed experiments build on our exciting preliminary results that generated innovative
new hypotheses about mechanisms of zinc homeostasis. I will directly test these hypotheses in worms and
human cells. Aberrant zinc accumulation is implicated in several human diseases, and the results may suggest
new therapeutic strategies for addressing disorders of zinc metabolism in humans.
锌是人体必需的营养素,必须严格控制,因为锌过量和缺乏都是
有害的锌稳态的复杂机制使动物能够感知和应对失衡
在细胞水平上的锌。然而,对这些机制的理解仍然不完整。我们最近
蛔虫C.线虫提出了锌稳态机制的新模型
对人类生物学有着重要意义。C.秀丽线虫已被证明是一种理想的模式生物,
锌生物学的研究,由于新的方法在操纵饮食锌的媒体,新描述的金属,
相关的表型,以及蠕虫群落中常见的遗传操作。在这个系统中,我们发现
高锌激活(HZA)元件介导多个基因的转录反应,
对高锌饮食的反应。此外,我们发现了高锌激活核受体(HIZR-1),
是锌稳态的主要调节因子,因为hizr-1(LF)突变体不能诱导锌应答基因,
突变体对锌毒性过敏。HIZR-1 DNA结合结构域(DBD)直接结合HZA,
HIZR-1配体结合结构域(LBD)直接结合锌。HIZR-1对高膳食锌的反应是:
聚集在细胞核中。最有趣的是,嵌合Gal 4(DBD)::HIZR-1(LBD)融合蛋白赋予
人类细胞培养中的锌反应。这些观察结果提出了两个令人兴奋的假设:(1)HIZR-1
对高水平的锌有反应,因为配体中的特定半胱氨酸、组氨酸和/或酸性氨基酸-
结合域直接配位锌。(2)人类细胞中的高锌稳态反应受以下因素调节:
hizr-1的功能性人类直系同源物。我将测试这些假设,(1)定义锌的机制
通过HIZR-1配体结合结构域的结构-功能分析来确定结合,以及(2)确定是否人
孤儿核受体在体内外通过与锌直接结合来感受高锌。这些研究报告将
通过定义新型高锌传感器的作用机制并可能识别人类而产生影响
高锌传感器与治疗锌稳态异常人类疾病有关。的能力
动物感知高和低的饮食锌并通过调节吸收、储存和排泄做出反应是至关重要的
来保持体内平衡拟议的实验建立在我们令人兴奋的初步结果的基础上,
锌稳态机制的新假说。我将直接在蠕虫中测试这些假设,
人类细胞。异常锌积累与几种人类疾病有关,结果可能表明,
用于解决人类锌代谢紊乱的新治疗策略。
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 }}
Brian James Earley其他文献
Brian James Earley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
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:
$ 2.9万 - 项目类别:
Fellowship
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:
$ 2.9万 - 项目类别:
Continuing Grant
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:
$ 2.9万 - 项目类别:
Research 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:
$ 2.9万 - 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:
$ 2.9万 - 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:
$ 2.9万 - 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:
$ 2.9万 - 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:
$ 2.9万 - 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:
$ 2.9万 - 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:
$ 2.9万 - 项目类别:
Research Grant