Mitochondrial respiratory chain disease mechanistic and therapeutic modeling
线粒体呼吸链疾病机制和治疗模型
基本信息
- 批准号:10569023
- 负责人:
- 金额:$ 58.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AcuteAffectAgeAnimal ModelAreaBasic ScienceBiochemicalBiochemical PathwayCaenorhabditis elegansCell modelCellsClinicalClinical TrialsCollectionDiseaseDisease modelDown SyndromeEducational process of instructingEtiologyFDA approvedFibroblastsFunctional disorderGenesGenetic DiseasesGenomeHealthHumanInternationalInvertebratesInvestigationLeadMacronutrients NutritionMedicineMethodologyMitochondriaMitochondrial ProteinsModelingMolecularNational Institute of General Medical SciencesNuclearNutritional SupportOrganPathogenicityPatientsPhenotypePost-Translational Protein ProcessingPrecision therapeuticsProductivityResearchResearch PersonnelRespiratory ChainSignal TransductionStressSystemTherapeuticValidationVariantVitaminsZebrafishcofactordetection of nutrientdisorder subtypeeffective therapyglycosylationhigh-throughput drug screeningimprovedin vivoinsightnanosensorsnovelnovel therapeuticspre-clinicalprecision medicineprogramsproteotoxicitytherapeutic candidatetherapeutic targettranslational research program
项目摘要
PROJECT SUMMARY. Mitochondrial respiratory chain (RC) diseases are highly morbid energy deficiency
disorders with remarkably heterogeneous etiologies and phenotypes across all ages and systems, caused by
pathogenic variants in > 350 different genes across both genomes. No cure, FDA-approved, nor clinical trial-
validated therapies exists for RC diseases. As one-size-fits-all, single therapy is unlikely to benefit all patients,
therapeutic modeling is essential to develop precision medicines that meaningful improve health in distinct
molecular, biochemical, or clinical RC disease subtypes. Specifically, pre-clinical translational RC disease
investigations in human patient cells and simple animal models may efficiently identify potent therapeutic
leads, and specific mechanistic targets, to meaningfully improve overall health. With our unique collection of
‘matched’ nuclear gene-based RC disease model sets (for NDUFS2, NUBPL, SURF1, FBXL4, C12ORF65,
DLD) across 3 evolutionarily distinct species in C. elegans (worm, invertebrate), D. rerio (zebrafish, vertebrate),
and human patient fibroblasts in which we have validated a suite of novel methodologies, we are strongly
situated to further harness a multi-species modeling approach. Indeed, we have established a highly
productive research program in RC disease models to cross-validate multiple mechanistic insights and identify
promising new therapeutic leads for primary RC diseases. NIGMS R35 MIRA support will enable focus of this
basic and translational research program with demonstrated teaching opportunities, as built over the past 14
years by an internationally-recognized investigator, to advance precision Mitochondrial Medicine by identifying
central disease mechanisms and lead therapeutic candidates for diverse RC disease subtypes. Specifically,
this translational research program will focus on harnessing RC disease patient cell and simple animal models
to investigate key questions across 2 overarching themes. Theme 1 is Pathophysiology Investigations,
involving 4 project areas: (i) Understanding the mechanistic basis by which different organ pathophysiology
predominates in distinct RC diseases, (ii) Developing sensitive nanosensors to non-invasively quantify in vivo
mitochondrial functions, (iii) Deciphering the functional significance of novel post-translational modifications,
including N-glycosylation, of mitochondrial proteins in RC disease, and (iv) Determining which central nutrient-
sensing signaling network (NSSN) node(s), and their downstream biochemical pathways that regulate cellular
proteotoxic stress, to therapeutically target in specific RC disease subsets. Theme 2 is Therapeutic Modeling,
involving 3 project areas: (v) Recognizing the optimal nutritional therapies (macronutrients, vitamins, cofactors)
to improve health and overall function in RC disease, (vi) Harnessing translational animal and cellular models
for high-throughput drug screening and lead compound validation, to efficiently identify highly potent, safe, and
precision therapies for distinct RC disease subgroups, and (vii) Identifying whether primary RC disease
treatments will improve health in disorders with secondary (such as Trisomy 21) or acute RC dysfunction.
项目摘要。线粒体呼吸链(RC)疾病是高度病态的能量缺乏
在所有年龄和系统中具有显著异质性病因和表型的疾病,由以下原因引起:
两个基因组中> 350个不同基因的致病性变体。没有治愈方法,FDA批准,也没有临床试验-
对于RC疾病存在有效的疗法。由于一刀切,单一疗法不太可能使所有患者受益,
治疗建模对于开发精确的药物至关重要,这些药物可以显著改善健康状况,
分子、生物化学或临床RC疾病亚型。具体而言,临床前转化性RC疾病
在人类患者细胞和简单的动物模型中的研究可以有效地鉴定有效的治疗方法,
引导和具体的机械目标,以有意义地改善整体健康。凭借我们独特的
“匹配的”基于核基因的RC疾病模型组(对于NDUFS 2,NUBPL,SURF 1,FBXL 4,C12 ORF 65,
DLD)在3个进化上不同的种间的差异。elegans(worm,invertebrate),D.鱼(斑马鱼,脊椎动物),
和人类患者成纤维细胞,我们已经验证了一套新的方法,我们强烈
以进一步利用多物种建模方法。我确已建立了一个高度的
RC疾病模型的生产性研究计划,以交叉验证多种机制的见解,并确定
有前途的新的治疗线索,为原发性RC疾病。NIGMS R35 MIRA支持将使重点放在这一点上
基础和转化研究计划与证明教学机会,如建立在过去14
由国际公认的研究人员,以推进精密线粒体医学,通过识别
中心疾病机制和不同RC疾病亚型的主要治疗候选者。具体地说,
这项转化研究计划将侧重于利用RC疾病患者细胞和简单的动物模型
调查两个重要主题的关键问题。主题1是病理生理学研究,
涉及4个项目领域:(i)了解不同器官病理生理学
在不同的RC疾病中占主导地位,(ii)开发敏感的纳米传感器,以非侵入性地在体内定量
线粒体功能,(iii)破译新的翻译后修饰的功能意义,
包括N-糖基化,以及(iv)确定哪种中心营养素-
传感信号网络(NSSN)节点,以及它们调节细胞内信号传导的下游生物化学途径。
蛋白毒性应激,以治疗特定RC疾病亚群。主题2是治疗建模,
涉及3个项目领域:㈤确认最佳营养疗法(常量营养素、维生素、辅因子)
改善RC疾病的健康和整体功能,(vi)利用转化动物和细胞模型
用于高通量药物筛选和先导化合物验证,以有效地鉴定高效、安全、
精确治疗不同的RC疾病亚组,和(vii)确定原发性RC疾病是否
治疗将改善具有继发性(如21三体)或急性RC功能障碍的疾病的健康。
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 }}
MARNI J FALK其他文献
MARNI J FALK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('MARNI J FALK', 18)}}的其他基金
Administrative Supplement for Leigh Syndrome Spectrum Expert Panel Curation
利氏综合征谱专家小组管理的行政补充
- 批准号:
10225911 - 财政年份:2020
- 资助金额:
$ 58.08万 - 项目类别:
Administrative Supplement - Mitochondrial respiratory chain disease mechanistic and therapeutic modeling
行政补充-线粒体呼吸链疾病机制和治疗模型
- 批准号:
10798475 - 财政年份:2020
- 资助金额:
$ 58.08万 - 项目类别:
Mitochondrial respiratory chain disease mechanistic and therapeutic modeling
线粒体呼吸链疾病机制和治疗模型
- 批准号:
10343742 - 财政年份:2020
- 资助金额:
$ 58.08万 - 项目类别:
Administrative Supplement (Undergraduate Summer Research Experiences) - Mitochondrial respiratory chain disease mechanistic and therapeutic modeling
行政补充(本科生暑期研究经历)-线粒体呼吸链疾病机制和治疗模型
- 批准号:
10809930 - 财政年份:2020
- 资助金额:
$ 58.08万 - 项目类别:
Primary Mitochondrial Disease Expert Curation Panel
原发性线粒体疾病专家小组
- 批准号:
10696934 - 财政年份:2017
- 资助金额:
$ 58.08万 - 项目类别:
Primary Mitochondrial Disease Expert Curation Panel
原发性线粒体疾病专家小组
- 批准号:
10173437 - 财政年份:2017
- 资助金额:
$ 58.08万 - 项目类别:
Primary Mitochondrial Disease Expert Curation Panel
原发性线粒体疾病专家小组
- 批准号:
10480773 - 财政年份:2017
- 资助金额:
$ 58.08万 - 项目类别:
相似海外基金
Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
- 批准号:
495182 - 财政年份:2023
- 资助金额:
$ 58.08万 - 项目类别:
Investigating how alternative splicing processes affect cartilage biology from development to old age
研究选择性剪接过程如何影响从发育到老年的软骨生物学
- 批准号:
2601817 - 财政年份:2021
- 资助金额:
$ 58.08万 - 项目类别:
Studentship
RAPID: Coronavirus Risk Communication: How Age and Communication Format Affect Risk Perception and Behaviors
RAPID:冠状病毒风险沟通:年龄和沟通方式如何影响风险认知和行为
- 批准号:
2029039 - 财政年份:2020
- 资助金额:
$ 58.08万 - 项目类别:
Standard Grant
Neighborhood and Parent Variables Affect Low-Income Preschool Age Child Physical Activity
社区和家长变量影响低收入学龄前儿童的身体活动
- 批准号:
9888417 - 财政年份:2019
- 资助金额:
$ 58.08万 - 项目类别:
The affect of Age related hearing loss for cognitive function
年龄相关性听力损失对认知功能的影响
- 批准号:
17K11318 - 财政年份:2017
- 资助金额:
$ 58.08万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
10166936 - 财政年份:2017
- 资助金额:
$ 58.08万 - 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
9320090 - 财政年份:2017
- 资助金额:
$ 58.08万 - 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
9761593 - 财政年份:2017
- 资助金额:
$ 58.08万 - 项目类别:
How age dependent molecular changes in T follicular helper cells affect their function
滤泡辅助 T 细胞的年龄依赖性分子变化如何影响其功能
- 批准号:
BB/M50306X/1 - 财政年份:2014
- 资助金额:
$ 58.08万 - 项目类别:
Training Grant
Inflamm-aging: What do we know about the effect of inflammation on HIV treatment and disease as we age, and how does this affect our search for a Cure?
炎症衰老:随着年龄的增长,我们对炎症对艾滋病毒治疗和疾病的影响了解多少?这对我们寻找治愈方法有何影响?
- 批准号:
288272 - 财政年份:2013
- 资助金额:
$ 58.08万 - 项目类别:
Miscellaneous Programs