Mechanisms of HIF1 alpha mediated dysregulated skeletal muscle proteostasis in alcoholic liver disease
HIF1α介导的酒精性肝病骨骼肌蛋白稳态失调的机制
基本信息
- 批准号:10579341
- 负责人:
- 金额:$ 17.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-01 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAdverse effectsAlcohol consumptionAlcoholic Liver CirrhosisAlcoholic Liver DiseasesAlcoholsAmmoniaAutophagocytosisAwardBiological AssayBiopsy SpecimenCareer ChoiceChromatinChronic DiseaseCirrhosisCitric Acid CycleClinicalCollaborationsComplexDataDegradation PathwayDevelopmentEnvironmentEthanolExposure toFRAP1 geneFellowshipFoundationsFundingGenetic TranscriptionGoalsHIF1A geneHeart failureHepaticHumanHyperammonemiaHypoxiaHypoxia Inducible FactorImpairmentIn VitroInstitutionKidney FailureLabelLinkLiver diseasesMediatingMentorsMetabolicMolecularMolecular TargetMorbidity - disease rateMusMuscleMuscle FibersMuscle ProteinsMuscular AtrophyNational Institute on Alcohol Abuse and AlcoholismOhioOutcomeOxygenPatientsPhenotypePhosphotransferasesPhysiciansPhysiologicalPilot ProjectsPost-Translational Protein ProcessingPre-Clinical ModelPrevalenceProtein BiosynthesisReporterReportingResearchResearch MethodologyResearch PersonnelResearch Project GrantsScientistSignal TransductionSignaling MoleculeSkeletal MuscleStressTestingTimeTissuesTrainingTranslational ResearchTransposaseUnited StatesValidationWorkalcohol consequencesalcohol exposurealcohol responsealcohol testingalcohol use disorderalpha ketoglutaratebiobankcareer developmentclinical trainingclinical translationclinically significanteffective therapyexperimental studygain of functionhepatic ureagenesisin vivoinhibitorliver transplantationloss of functionlung failuremetabolic abnormality assessmentmitochondrial dysfunctionmortalitymuscle formmuscle strengthnovelpreservationprogramsproteostasisresponsesarcopeniaskeletal muscle wastingtargeted treatmenttherapeutically effectivetissue injurytranscription factoruptake
项目摘要
The prevalence of alcohol use disorders and consequent tissue injury, primarily alcoholic liver disease (ALD)
continue to increase. Skeletal muscle loss or sarcopenia is a consistent abnormality in patients with ALD and is
associated with adverse clinical outcomes that include increased mortality, other complications of liver disease
and poor post-liver transplant outcomes. We have recently reported more severe muscle loss and a greater
rate of muscle loss in patients with alcoholic cirrhosis compared with those in other causes of cirrhosis. Despite
the high clinical significance of sarcopenia in ALD there are no effective therapeutic options because the
underlying mechanisms are not well understood. We also reported that ethanol, directly and indirectly via
impaired hepatic ammonia disposal and consequent hyperammonemia, results in a sarcopenic phenotype with
dysregulated protein homeostasis (proteostasis). In preliminary studies, we have shown mitochondrial
dysfunction in response to ethanol and hyperammonemia. We also noted that ethanol results in cataplerosis or
loss of tricarboxylic acid (TCA) cycle intermediates, specifically α-ketoglutarate (αKG) an inhibitor of HIF1α.
Consistently, unbiased approaches (assay for transposase accessible chromatin sequencing), and targeted
experiments showed oxygen independent stabilization of muscle hypoxia inducible factor-1α (HIF1α) with
ammonia. In pilot studies, we observed an increased expression of REDD1, a transcriptional target of HIF1α
and a negative regulator of the mammalian target of rapamycin complex 1 (mTORC1) that maintains skeletal
muscle proteostasis with functional responses. We also noted relative preservation of muscle mass during
hyperammonemia in muscle specific deletion of HIF1α mice. These observations formed the basis for our
hypothesis that ethanol induced hyperammonemia causes cataplerosis of αKG with oxygen independent
stabilization and impaired proteostasis and sarcopenia. We will test this hypothesis by testing if ethanol
stabilizes HIF1α in skeletal muscle, and determine the mechanisms of stabilization of muscle HIF1α. Ethanol
treatment in vitro in myotubes and in vivo in mice with loss and gain of function of HIF1α and its regulatory
molecules will be used for these studies We will also test how metabolic perturbations regulate HIF1α
stabilization and consequent molecular and functional responses in our preclinical models. Validation of key
observations will be done in human muscle tissue from our biorepository. The proposed studies will enhance
our understanding of the mechanisms of sarcopenia in ALD and lay the foundation for targeted therapeutics.
This award will provide the support and time for the applicant for a supervised research career development in
translational research. The applicant works with NIAAA funded independent investigators in the Northern Ohio
Alcohol Center and her mentor developed the field of sarcopenia in liver disease. The institutional environment
is highly supportive of her career path towards becoming an independent physician scientist focusing on
mechanistic approaches to address unmet clinical needs in patients with alcohol use disorders.
酒精使用障碍和随之而来的组织损伤的患病率,主要是酒精性肝病(ALD)
继续增加。骨骼肌丢失或肌肉减少症是酒精性肝脏疾病患者的持续异常,并且
与不良临床结局相关,包括死亡率增加,肝病的其他并发症
以及肝脏移植后的不良结果。我们最近报道了更严重的肌肉损失和更大的
酒精性肝硬化患者与其他原因肝硬化患者相比的肌肉损失率。尽管
ALD中肌肉减少症的高度临床意义,没有有效的治疗选择,
根本的机制还不清楚。我们还报告说,乙醇,直接和间接通过
受损的肝氨处理和随后的高氨血症,导致肌肉减少表型,
蛋白质稳态失调(Proteostasis)。在初步研究中,我们发现线粒体
对乙醇和高氨血症的反应性功能障碍。我们还注意到,乙醇会导致细胞增殖,
三羧酸(TCA)循环中间体的损失,特别是HIF 1 α抑制剂α-酮戊二酸(αKG)。
一致的、无偏倚的方法(转座酶可及染色质测序测定),
实验表明,肌肉缺氧诱导因子-1 α(HIF 1 α)的氧非依赖性稳定,
氨在初步研究中,我们观察到HIF 1 α的转录靶点REDD 1的表达增加,
和雷帕霉素复合物1的哺乳动物靶蛋白(mTORC 1)的负调节因子,其维持骨骼肌
肌肉蛋白质稳态与功能反应。我们还注意到,
肌肉特异性缺失HIF 1 α小鼠高氨血症这些观察形成了我们的基础。
乙醇诱导高氨血症导致αKG分解与氧非依赖假说
稳定性和蛋白质稳态受损以及肌肉减少症。我们将通过测试乙醇是否
稳定骨骼肌中的HIF 1 α,并确定肌肉HIF 1 α的稳定机制。乙醇
在肌管中的体外治疗和在具有HIF 1 α及其调节功能的丧失和获得的小鼠中的体内治疗
我们还将测试代谢扰动如何调节HIF 1 α
稳定和随后的分子和功能反应。密钥验证
将在我们生物库的人类肌肉组织中进行观察。拟议的研究将加强
为进一步了解ALD患者肌肉减少症的发病机制和靶向治疗奠定基础。
该奖项将为申请人提供支持和时间,以监督研究职业发展,
翻译研究申请人与NIAAA资助的北方俄亥俄州独立调查人员合作
酒精中心和她的导师开发了肝脏疾病中的肌肉减少症领域。制度环境
高度支持她的职业道路,成为一名独立的医生科学家,
机械方法,以解决酒精使用障碍患者未满足的临床需求。
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 }}
Nicole Welch其他文献
Nicole Welch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('Nicole Welch', 18)}}的其他基金
Mechanisms of HIF1 alpha mediated dysregulated skeletal muscle proteostasis in alcoholic liver disease
HIF1α介导的酒精性肝病骨骼肌蛋白稳态失调的机制
- 批准号:
10358594 - 财政年份:2021
- 资助金额:
$ 17.91万 - 项目类别:
相似海外基金
Unraveling Adverse Effects of Checkpoint Inhibitors Using iPSC-derived Cardiac Organoids
使用 iPSC 衍生的心脏类器官揭示检查点抑制剂的副作用
- 批准号:
10591918 - 财政年份:2023
- 资助金额:
$ 17.91万 - 项目类别:
Optimization of mRNA-LNP vaccine for attenuating adverse effects and analysis of mechanism behind adverse effects
mRNA-LNP疫苗减轻不良反应的优化及不良反应机制分析
- 批准号:
23K15383 - 财政年份:2023
- 资助金额:
$ 17.91万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of adverse effects of combined exposure to low-dose chemicals in the living environment on allergic diseases and attempts to reduce allergy
阐明生活环境中低剂量化学品联合暴露对过敏性疾病的不良影响并尝试减少过敏
- 批准号:
23H03556 - 财政年份:2023
- 资助金额:
$ 17.91万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Green tea-based nano-enhancer as an adjuvant for amplified efficacy and reduced adverse effects in anti-angiogenic drug treatments
基于绿茶的纳米增强剂作为抗血管生成药物治疗中增强疗效并减少不良反应的佐剂
- 批准号:
23K17212 - 财政年份:2023
- 资助金额:
$ 17.91万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Effects of Tobacco Heating System on the male reproductive function and towards to the reduce of the adverse effects.
烟草加热系统对男性生殖功能的影响以及减少不利影响。
- 批准号:
22H03519 - 财政年份:2022
- 资助金额:
$ 17.91万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Mitigating the Adverse Effects of Ultrafines in Pressure Filtration of Oil Sands Tailings
减轻油砂尾矿压力过滤中超细粉的不利影响
- 批准号:
563657-2021 - 财政年份:2022
- 资助金额:
$ 17.91万 - 项目类别:
Alliance Grants
1/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
1/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10521849 - 财政年份:2022
- 资助金额:
$ 17.91万 - 项目类别:
4/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
4/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10671022 - 财政年份:2022
- 资助金额:
$ 17.91万 - 项目类别:
2/4 Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
2/4 ECT 结果和不良反应的破译机制(DECODE)
- 批准号:
10670918 - 财政年份:2022
- 资助金额:
$ 17.91万 - 项目类别:
Downsides of downhill: The adverse effects of head vibration associated with downhill mountain biking on visuomotor and cognitive function
速降的缺点:与速降山地自行车相关的头部振动对视觉运动和认知功能的不利影响
- 批准号:
2706416 - 财政年份:2022
- 资助金额:
$ 17.91万 - 项目类别:
Studentship