Benefits and harms of activating ATF6 in beta cells
激活 β 细胞中 ATF6 的好处和坏处
基本信息
- 批准号:10608568
- 负责人:
- 金额:$ 45.57万
- 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:2023-01-01 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:ATF6 geneAttentionAutomobile DrivingBeta CellBiologyCell CountCell ProliferationCell SurvivalCell physiologyCellular StressChronicClustered Regularly Interspaced Short Palindromic RepeatsDHFR geneDataData SetDiabetes MellitusDiseaseEngineeringExposure toFailureFrustrationFunctional disorderFutureGeneticGenetic TranscriptionGenomicsGlucoseGlucose IntoleranceGoalsHarm ReductionHealthHomeostasisHourHumanImpairmentInsulinInsulin-Dependent Diabetes MellitusIslet CellLasersLeadLearningLinkModelingMolecularMorphologyMusNon-Insulin-Dependent Diabetes MellitusPathway interactionsPharmaceutical PreparationsPlayPopulationPredispositionPreventionProcessProductionProliferatingProteinsPublishingRecoveryReportingResistanceRiskRoleStimulusStressStructure of beta Cell of isletSystemTechnologyTestingTherapeuticTimeTissuesUncertaintyWorkbasebiological adaptation to stresscell typecombatdiabetes pathogenesisdiabetes riskdiabeticdiabetogenicendoplasmic reticulum stressexperimental studygenomic locusimprovedin vivoinsightisletnovelnovel strategiespreventresilienceresponsesmall moleculetooltranscription factor
项目摘要
ABSTRACT
Pancreatic beta cell insulin production is the critical lynchpin that determines diabetes resistance or susceptibility.
ER stress is one cause of beta cell dysfunction and failure, not only in T2D but also in T1D and some forms of
monogenic diabetes. Many published reports show that the ATF6 pathway, one of three principal ER stress
response pathways, plays important roles in cellular adaptation to stress. In particular, ATF6 is known to drive
beneficial effects including increased ER capacity, cell survival in the face of stress, and more recently evidence
from our group and several others implicate ATF6 in beta cell compensatory proliferation in response to insulin
demand. For these reasons, activation of ATF6 has been proposed as a potential beta cell therapeutic approach
that might improve beta cell mass and insulin production capacity. We have developed two novel, exciting tools
that allow us to activate ATF6 in beta cells with temporal precision, either ex vivo or in vivo in live mice. Initial
experiments, however, show that when we indiscriminately activate ATF6 for an extended period of time we
observe a mix of beneficial and harmful effects, in some ways reminiscent of glucotoxic beta cell failure.
Specifically, we do observe evidence of increased beta cell proliferation and survival, but activating ATF6 in vivo
continuously for a 14-day period leads to frank glucose intolerance due to beta cell dysfunction. Remarkably, if
we allow ATF6 to turn off, beta cell function gradually returns to normal. Molecular and morphological preliminary
data suggest that in vivo chronic continuous ATF6 activation mimics, in many ways, chronic beta cell stress in
T2D, with similarities to mouse and human observations. As such, this model represents a tremendous
opportunity to study the proximate causes of beta cell failure after chronic activation of one ER stress response
pathway (ATF6), as well as a unique and exciting chance to understand the in vivo recovery process if that stress
pathway activation is able to shut off. In this project we will explore the causes of beta cell failure after ATF6
activation, with in-depth molecular, morphological and tissue homeostasis experiments. We will determine the
cellular and molecular bases for beta cell recovery when ATF6 is allowed to turn off. Finally, we turn our attention
to the molecular mechanisms driving benefits and harms of ATF6 activation and seek to identify conditions in
which beneficial responses can be separated from harmful responses, to see whether it may be possible in the
future to harness ATF6 for safe therapeutic potential in diabetes treatment or prevention. If successful, this
project will lead to important new insight into beta cell stress-induced diabetes, the in vivo recovery process after
ATF6-induced beta cell dysfunction, the molecular mechanisms by which ATF6 drives benefits and harms, and
whether it may be possible to separate benefit from harm for future therapeutic benefit.
摘要
胰腺β细胞胰岛素的产生是决定糖尿病抵抗或易感性的关键。
ER应激是β细胞功能障碍和衰竭的原因之一,不仅在T2D中,而且在T1D和某些形式的
单基因糖尿病许多已发表的报告表明,三种主要的ER应激之一的ATF6途径,
反应途径,在细胞适应压力中起着重要作用。具体地,已知ATF 6驱动
有益的影响,包括增加ER能力,细胞在面对压力时的存活,以及最近的证据
来自我们小组和其他几个小组的研究表明,ATF6参与了β细胞对胰岛素应答的代偿性增殖
需求由于这些原因,已经提出激活ATF6作为潜在的β细胞治疗方法
这可能会提高β细胞质量和胰岛素生产能力。我们开发了两种新颖的令人兴奋的工具
这使得我们能够在离体或活小鼠体内以时间精确度激活β细胞中的ATF6。初始
然而,实验表明,当我们不加选择地激活ATF6一段时间后,
观察有益和有害的影响,在某些方面让人想起葡萄糖毒性β细胞衰竭。
具体地说,我们确实观察到β细胞增殖和存活增加的证据,但在体内激活了ATF 6,
连续14天导致由于β细胞功能障碍而导致的明显的葡萄糖耐受不良。值得注意的是,如果
我们让ATF6关闭,β细胞功能逐渐恢复正常。分子和形态学初步
数据表明,在体内慢性持续的ATF6活化在许多方面模拟了慢性β细胞应激,
T2D,与小鼠和人类观察结果相似。因此,这种模式代表了一种巨大的
有机会研究一种ER应激反应慢性激活后β细胞衰竭的近因
途径(ATF6),以及一个独特的和令人兴奋的机会,了解体内恢复过程,如果压力
通路激活能够被关闭。在这个项目中,我们将探讨ATF6后β细胞衰竭的原因。
通过深入的分子、形态学和组织稳态实验,康贝特人将以
当允许关闭ATF6时,β细胞恢复的细胞和分子基础。最后,我们把注意力
了解驱动ATF 6激活的益处和危害的分子机制,并寻求确定其中的条件
哪些有益的反应可以从有害的反应中分离出来,看看是否有可能在
未来利用ATF 6在糖尿病治疗或预防中的安全治疗潜力。如果成功,这
该项目将导致对β细胞应激诱导的糖尿病的重要新见解,在体内恢复过程后,
ATF6诱导的β细胞功能障碍,ATF6驱动益处和危害的分子机制,以及
是否有可能为了将来的治疗益处而将益处与危害分开。
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 }}
Laura C Alonso其他文献
Genetic and Metabolic Determinants of Lipoprotein(a)
- DOI:
10.1016/j.jacl.2023.05.009 - 发表时间:
2023-07-01 - 期刊:
- 影响因子:
- 作者:
Sarah L Stewart;Oleksandr Savenkov;Maurice A Hurd;Amanda Halstrom;John Falcone;Katerine Claudio;Jyothi Manohar;Fana Dealla;Sonal Kumar;Jessica M Peña;Michele Yeung;Judy Tung;Greg Dakin;Esther Wei;Lisa C Hudgins;Laura C Alonso;Shuibing Chen;Marcus D Goncalves - 通讯作者:
Marcus D Goncalves
Laura C Alonso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('Laura C Alonso', 18)}}的其他基金
Research Training in Endocrinology and Metabolism
内分泌学和代谢研究培训
- 批准号:
10627311 - 财政年份:2023
- 资助金额:
$ 45.57万 - 项目类别:
Role of Polyamines and Hypusine in Nutrient-Induced Beta-Cell Growth and Replication
多胺和马尿苷在营养诱导的 β 细胞生长和复制中的作用
- 批准号:
10160901 - 财政年份:2020
- 资助金额:
$ 45.57万 - 项目类别:
Role of Polyamines and Hypusine in Nutrient-Induced Beta-Cell Growth and Replication
多胺和马尿苷在营养诱导的 β 细胞生长和复制中的作用
- 批准号:
9981964 - 财政年份:2020
- 资助金额:
$ 45.57万 - 项目类别:
Role of Polyamines and Hypusine in Nutrient-Induced Beta-Cell Growth and Replication
多胺和马尿苷在营养诱导的 β 细胞生长和复制中的作用
- 批准号:
10399647 - 财政年份:2020
- 资助金额:
$ 45.57万 - 项目类别:
Role of Polyamines and Hypusine in Nutrient-Induced Beta-Cell Growth and Replication
多胺和马尿苷在营养诱导的 β 细胞生长和复制中的作用
- 批准号:
10613949 - 财政年份:2020
- 资助金额:
$ 45.57万 - 项目类别:
Role of GRP78 in beta cell adaptation in obesity and diabetes
GRP78 在肥胖和糖尿病的 β 细胞适应中的作用
- 批准号:
10085817 - 财政年份:2018
- 资助金额:
$ 45.57万 - 项目类别:
Free Fatty Acids, p16 and Pancreatic Beta Cell Proliferation
游离脂肪酸、p16 和胰腺 β 细胞增殖
- 批准号:
8271681 - 财政年份:2012
- 资助金额:
$ 45.57万 - 项目类别:
相似国自然基金
多模态超声VisTran-Attention网络评估早期子宫颈癌保留生育功能手术可行性
- 批准号:
- 批准年份:2022
- 资助金额:30 万元
- 项目类别:青年科学基金项目
Ultrasomics-Attention孪生网络早期精准评估肝内胆管癌免疫治疗的研究
- 批准号:
- 批准年份:2022
- 资助金额:52 万元
- 项目类别:面上项目
相似海外基金
Development of social attention indicators of emerging technologies and science policies with network analysis and text mining
利用网络分析和文本挖掘开发新兴技术和科学政策的社会关注指标
- 批准号:
24K16438 - 财政年份:2024
- 资助金额:
$ 45.57万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Improving Flexible Attention to Numerical and Spatial Magnitudes in Young Children
提高幼儿对数字和空间大小的灵活注意力
- 批准号:
2410889 - 财政年份:2024
- 资助金额:
$ 45.57万 - 项目类别:
Continuing Grant
The Information-Attention Tradeoff: Toward an Understanding of the Fundamentals of Online Attention
信息与注意力的权衡:了解在线注意力的基本原理
- 批准号:
2343858 - 财政年份:2024
- 资助金额:
$ 45.57万 - 项目类别:
Continuing Grant
The everyday learning opportunities of young children with attention and motor difficulties: From understanding constraints to reshaping intervention
注意力和运动困难幼儿的日常学习机会:从理解限制到重塑干预
- 批准号:
MR/X032922/1 - 财政年份:2024
- 资助金额:
$ 45.57万 - 项目类别:
Fellowship
Towards a cognitive process model of how attention and choice interact
建立注意力和选择如何相互作用的认知过程模型
- 批准号:
DP240102605 - 财政年份:2024
- 资助金额:
$ 45.57万 - 项目类别:
Discovery Projects
DDRIG in DRMS: Communicating risks in a sensational media environment-Using short video multimodal features to attract attention and reduce psychological reactance for persuasion
DRMS中的DDRIG:耸人听闻的媒体环境中沟通风险——利用短视频多模态特征吸引注意力,减少说服心理抵触
- 批准号:
2343506 - 财政年份:2024
- 资助金额:
$ 45.57万 - 项目类别:
Standard Grant
Assessing the Influence of Reading Fiction on Multiple Tests of Attention
评估阅读小说对注意力多重测试的影响
- 批准号:
24K16033 - 财政年份:2024
- 资助金额:
$ 45.57万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
CAREER: Designing Ultra-Energy-Efficient Intelligent Hardware with On-Chip Learning, Attention, and Inference
职业:设计具有片上学习、注意力和推理功能的超节能智能硬件
- 批准号:
2336012 - 财政年份:2023
- 资助金额:
$ 45.57万 - 项目类别:
Continuing Grant
CPS: Small: Brain-Inspired Memorization and Attention for Intelligent Sensing
CPS:小:智能传感的受大脑启发的记忆和注意力
- 批准号:
2312517 - 财政年份:2023
- 资助金额:
$ 45.57万 - 项目类别:
Standard Grant
CAREER: Understanding the Relationship of Covert and Overt Attention Using Concurrent EEG and Eye Tracking
职业:使用并发脑电图和眼动追踪了解隐性注意力和显性注意力的关系
- 批准号:
2345898 - 财政年份:2023
- 资助金额:
$ 45.57万 - 项目类别:
Continuing Grant