Muscle GPRC6A regulation of protein turnover with overload and disuse recovery
肌肉 GPRC6A 对过载和废用恢复中蛋白质周转的调节
基本信息
- 批准号:10625420
- 负责人:
- 金额:$ 16.94万
- 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:2022-06-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationActivities of Daily LivingAdultAreaArginineAtrophicAttenuatedBiologyClinicalCommunicationCulture MediaDisuse AtrophyExerciseFatty LiverFemaleFoundationsG-Protein-Coupled ReceptorsGPRC6A geneGTP-Binding ProteinsGeneticGlucose IntoleranceGoalsGrowthGrowth FactorHealthHigh Fat DietHindlimb SuspensionHomeostasisHospitalizationHumanImmobilizationIn VitroInflammationInsulinInsulin ResistanceInterleukin-6InterventionInvestigationKnockout MiceKnowledgeLigandsLinkMaintenanceMechanicsMetabolicMetabolic hormoneMetabolic syndromeMetabolismModelingMolecularMusMuscleMuscle FibersMuscle ProteinsMuscular AtrophyObesityOrganOsteocalcinPathway interactionsPatientsPeptidesPeripheralPharmacologic SubstancePopulationProcessPropertyProteinsPublishingRecoveryRegulationResearchRoleSerumSignal TransductionSkeletal MuscleStretchingTestingTestosteroneTissuesautocrinecell typecytokinefibroblast growth factor 21glucagon-like peptide 1glucose toleranceimprovedin vitro Modelin vivoinsulin sensitivitylink proteinmalemuscle formmuscle metabolismnew therapeutic targetnovelnovel strategiesnovel therapeutic interventionnovel therapeuticsparacrinepharmacologicpre-clinicalpreventprotein degradationreceptorreduced muscle massresponsesedentary lifestyleskeletal muscle wastingsynergismtherapeutic target
项目摘要
Skeletal muscle mass maintenance is critical for metabolic health and functional capacity and becomes a
challenge during forced immobility or sedentary behavior. Despite progress in understanding the molecular
drivers of load-induced muscle growth, there remains a need for novel approaches and different mechanistic
paradigms to enhance muscle recovery from atrophy. Although load-induced muscle growth and recovery from
disuse muscle atrophy involve protein accretion, the growth processes differ in the extent of the remodeling,
damage, and inflammation present. We will mechanistically investigate a novel regulatory paradigm involved in
skeletal muscle mass and metabolism regulation to improve our understanding of recovery from disuse atrophy
and identify therapeutic targets for treating low muscle mass in patients. GPRC6A is a G-protein-linked
receptor expressed in many tissues, including skeletal muscle, and has multiple ligands, including the peptide
osteocalcin. Ligand activation of GPRC6A improves glucose tolerance and peripheral insulin sensitivity and
prevents high-fat diet-induced hepatosteatosis in mice. GPRC6A knockout mice manifest metabolic syndrome,
loss of muscle mass, glucose intolerance, and insulin resistance. There is evidence that signaling initiated by
the skeletal muscle GPRC6A receptor can regulate muscle growth and metabolism. However, skeletal muscle
GPRC6A's role in disuse atrophy and recovery is not known. Our investigative team’s synergistic expertise in
GPRC6A function, metabolism, in vitro myotube growth, in vivo preclinical disuse and recovery models, and
muscle biology provides a unique opportunity to study this novel regulatory paradigm. Our project's expected
results hold substantial potential for identifying therapeutic targets to benefit muscle accretion in low muscle
mass patients. The proposed study will provide foundational evidence for novel therapeutic paradigms to
improve skeletal muscle load sensitivity linked to disuse atrophy and recovery. Genetic and pharmacological
approaches will investigate GPRC6A regulation of muscle mass accretion and contractile function. Our central
hypothesis is that loss of skeletal muscle GPRC6A signaling will attenuate recovery from disuse atrophy in
male and female mice. Furthermore, GPRC6A activation by Ocn will accelerate the recovery of mass,
metabolic properties, and contractile function. Aim 1 will investigate muscle GPRC6A’s role in myotube growth
and atrophy in vitro. Established models of high serum media and stretch-induced growth in additional to
stretch-release to examine myotube atrophy will be used to assess effects on stretch and serum-induced
growth. Aim 2 will evaluate the role of GPRC6A signaling in disuse atrophy and the load-induced recovery of
muscle mass and contractile and metabolic function in vivo. Normal cage ambulation after hindlimb
suspension-induced disuse will examine recovery from atrophy. Our results will provide the foundation for
novel therapeutic approaches that activate GPRC6A via ligands such as testosterone or other pharmaceutical
interventions.
骨骼肌质量的维持对代谢健康和功能能力至关重要,
在强迫不动或久坐不动的行为中的挑战。尽管在了解分子生物学方面取得了进展,
尽管负荷诱导的肌肉生长的驱动因素,仍然需要新的方法和不同的机制,
范例,以增强肌肉从萎缩中恢复。虽然负荷引起的肌肉生长和恢复,
废用性肌肉萎缩涉及蛋白质增加,生长过程在重塑的程度上不同,
损伤和炎症。我们将机械地研究一种新的监管范式,
骨骼肌质量和代谢调节,以提高我们对废用性萎缩恢复的理解
并确定用于治疗患者低肌肉质量的治疗靶点。GPRC6A是一个G蛋白连接的
受体在包括骨骼肌在内的许多组织中表达,并具有多种配体,包括肽
骨钙素GPRC6A的配体活化改善葡萄糖耐量和外周胰岛素敏感性,
预防高脂饮食诱导的小鼠脂肪肝。GPRC6A敲除小鼠表现出代谢综合征,
肌肉质量损失、葡萄糖耐受不良和胰岛素抵抗。有证据表明,信号启动由
骨骼肌GPRC6A受体可调节肌肉生长和代谢。然而,骨骼肌
GPRC6A在废用性萎缩和恢复中的作用尚不清楚。我们的调查团队在以下方面的协同专业知识
GPRC6A功能、代谢、体外肌管生长、体内临床前废用和恢复模型,以及
肌肉生物学提供了一个独特的机会来研究这种新的监管模式。我们的项目
这些结果对于确定治疗靶点以在低肌生长中有益于肌肉生长具有很大的潜力。
大量患者。这项拟议的研究将为新的治疗范例提供基础证据,
改善与废用性萎缩和恢复相关骨骼肌负荷敏感性。遗传和药理学
方法将研究GPRC6A对肌肉质量增加和收缩功能的调节。我们的中央
假设骨骼肌GPRC6A信号传导的丧失将减弱从废用性萎缩中的恢复,
雄性和雌性小鼠。此外,Ocn激活GPRC6A将加速质量恢复,
代谢特性和收缩功能。目的1研究GPRC6A在肌管生长中的作用
和体外萎缩。建立了高血清培养基和拉伸诱导生长的模型,
拉伸释放检查肌管萎缩将用于评估对拉伸和血清诱导的肌管萎缩的影响。
增长目的2将评估GPRC6A信号在废用性萎缩和负荷诱导的恢复中的作用。
肌肉质量以及体内的收缩和代谢功能。后肢后正常笼状肌
悬浮诱导的废用将检查从萎缩的恢复。我们的研究结果将为
通过配体如睾酮或其它药物来激活GPRC6A的新的治疗方法
干预措施。
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 }}
James A Carson其他文献
James A Carson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('James A Carson', 18)}}的其他基金
Muscle GPRC6A regulation of protein turnover with overload and disuse recovery
肌肉 GPRC6A 对过载和废用恢复中蛋白质周转的调节
- 批准号:
10463302 - 财政年份:2022
- 资助金额:
$ 16.94万 - 项目类别:
(PQ 12) The Regulation of Physical Function and Skeletal Muscle Metabolic Signaling After Cessation of 5-Fluorouracil Treatment
(PQ 12) 停止 5-氟尿嘧啶治疗后身体功能和骨骼肌代谢信号的调节
- 批准号:
9927604 - 财政年份:2019
- 资助金额:
$ 16.94万 - 项目类别:
Cachexia in ApcMin/+ mice: The role of IL-6
ApcMin/ 小鼠恶病质:IL-6 的作用
- 批准号:
9251557 - 财政年份:2016
- 资助金额:
$ 16.94万 - 项目类别:
GUT BARRIER DYSFUNCTION: THE TRIGGER FOR CACHEXIA IN APCMIN/+ MICE
肠道屏障功能障碍:APCMIN/小鼠恶病质的触发因素
- 批准号:
7959766 - 财政年份:2009
- 资助金额:
$ 16.94万 - 项目类别:
Cachexia in ApcMin/+ mice: The role of IL-6
ApcMin/ 小鼠恶病质:IL-6 的作用
- 批准号:
7790516 - 财政年份:2008
- 资助金额:
$ 16.94万 - 项目类别:
Cachexia in ApcMin/+ mice: The role of IL-6
ApcMin/ 小鼠恶病质:IL-6 的作用
- 批准号:
7466689 - 财政年份:2008
- 资助金额:
$ 16.94万 - 项目类别:
Cachexia in ApcMin/+ mice: The role of IL-6
ApcMin/ 小鼠恶病质:IL-6 的作用
- 批准号:
9228937 - 财政年份:2008
- 资助金额:
$ 16.94万 - 项目类别:
Cachexia in ApcMin/+ mice: The role of IL-6
ApcMin/ 小鼠恶病质:IL-6 的作用
- 批准号:
8695594 - 财政年份:2008
- 资助金额:
$ 16.94万 - 项目类别:
Cachexia in ApcMin/+ mice: The role of IL-6
ApcMin/ 小鼠恶病质:IL-6 的作用
- 批准号:
9432821 - 财政年份:2008
- 资助金额:
$ 16.94万 - 项目类别:
Cachexia in ApcMin/+ mice: The role of IL-6
ApcMin/ 小鼠恶病质:IL-6 的作用
- 批准号:
7619472 - 财政年份:2008
- 资助金额:
$ 16.94万 - 项目类别:
相似海外基金
Determining 4-Dimensional Foot Loading Profiles of Healthy Adults across Activities of Daily Living
确定健康成年人日常生活活动的 4 维足部负荷曲线
- 批准号:
2473795 - 财政年份:2024
- 资助金额:
$ 16.94万 - 项目类别:
Studentship
Developing a trunk function assessment for hemiplegics. -For improving activities of daily living-
开发偏瘫患者的躯干功能评估。
- 批准号:
23K10540 - 财政年份:2023
- 资助金额:
$ 16.94万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Relation with the activities of daily living and the subjective values among people with social withdrawal
社交退缩者日常生活活动与主观价值观的关系
- 批准号:
23K16596 - 财政年份:2023
- 资助金额:
$ 16.94万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
CRII: RI: Understanding Activities of Daily Living in Indoor Scenarios
CRII:RI:了解室内场景中的日常生活活动
- 批准号:
2245652 - 财政年份:2023
- 资助金额:
$ 16.94万 - 项目类别:
Standard Grant
Association between Nursing Care and Prognosis and Activities of Daily Living in Acute Stroke patients by using Big Data.
利用大数据研究急性脑卒中患者的护理与预后和日常生活活动的关系。
- 批准号:
23K16412 - 财政年份:2023
- 资助金额:
$ 16.94万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Sources of vulnerability among those using homecare despite having no limitations in Activities of Daily Living. An intersectionality analysis
尽管日常生活活动没有限制,但使用家庭护理的人的脆弱性来源。
- 批准号:
499112 - 财政年份:2023
- 资助金额:
$ 16.94万 - 项目类别:
Operating Grants
Synergizing home health rehabilitation therapy to optimize patients’ activities of daily living
协同家庭健康康复治疗,优化患者的日常生活活动
- 批准号:
10429480 - 财政年份:2022
- 资助金额:
$ 16.94万 - 项目类别:
Effects of a model of nurses-occupational therapists collaborative practice on activities of daily living in elderly patients
护士-职业治疗师合作实践模式对老年患者日常生活活动的影响
- 批准号:
22K17540 - 财政年份:2022
- 资助金额:
$ 16.94万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Assessing a Novel Virtual Environment that Primes Individuals Living with AD/ADRD to Accomplish Activities of Daily Living.
评估一种新颖的虚拟环境,该环境可以帮助 AD/ADRD 患者完成日常生活活动。
- 批准号:
10668160 - 财政年份:2022
- 资助金额:
$ 16.94万 - 项目类别:
Synergizing home health rehabilitation therapy to optimize patients’ activities of daily living
协同家庭健康康复治疗,优化患者的日常生活活动
- 批准号:
10621820 - 财政年份:2022
- 资助金额:
$ 16.94万 - 项目类别: