Functional role and therapeutic targeting of exosomes and extracellular RNA biomarkers in heart failure
外泌体和细胞外 RNA 生物标志物在心力衰竭中的功能作用和治疗靶向
基本信息
- 批准号:9894484
- 负责人:
- 金额:$ 96.07万
- 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:2020-06-01 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAreaAutophagocytosisBiological MarkersBiologyCardiacCardiac MyocytesCardiovascular DiseasesCell Culture TechniquesCell physiologyCellsCessation of lifeClinicalComplexDiagnosisDiseaseFibrosisGrantHealth ExpendituresHeart HypertrophyHeart failureHospitalizationHumanInterruptionMeasuresMediatingMentorsModelingMorbidity - disease rateMusMyocardial InfarctionNuclearPathogenesisPatientsPerformancePhenotypePlasmaPlayPrevalenceProcessRNAResearchResearch PersonnelRisk stratificationRoleSamplingSignal PathwaySignal TransductionStructureTimeTissuesUnited StatesWorkbiobankclinical biomarkersclinically actionableexosomeexperimental studyextracellularextracellular vesiclesflexibilityhigh rewardhigh riskimprovedinduced pluripotent stem cellinsightintercellular communicationmortalitymouse modelnew therapeutic targetnext generationnovelnovel therapeuticsorgan on a chipprognosticsmall moleculetherapeutic siRNAtherapeutic targettooltranscriptome sequencinguptakevesicular release
项目摘要
Despite important advances in the treatment of heart failure (HF), >50% of patients die within 5 years of
diagnosis at their first hospital admission, and HF remains a leading cause of morbidity, mortality and
healthcare expenditure in the United States. With the prevalence of HF expected to increase to 46% by 2030,
novel mechanistic insight into HF pathogenesis and strategies to interrupt this progression are a large unmet
clinical need. My research has focused on the role of exosomes or extracellular vesicles (EVs) and their cargo
RNAs (EV-RNAs) as novel functional biomarkers. We have discovered and validated plasma RNA signatures
that correlate with human HF phenotypes such as adverse structural remodeling after myocardial infarction,
fibrosis and sudden arrhythmic death. We have shown that many of these plasma RNAs are sequestered
within EVs and are a novel mode of intercellular communication. Importantly, many of these EV-RNAs change
in parallel in cardiac tissue, modulating complex signaling pathways that may underlie HF pathogenesis. This
work affords a unique opportunity to develop i) novel clinically useful biomarkers for improved risk stratification
of HF patients; and ii) novel therapeutic targets to interrupt the adverse remodeling process.
I now seek to leverage the tools and platforms developed over the past 5 years to move the EV and EV-RNA
field in new directions using the flexible R35 grant mechanism. I seek to broadly address the following broad
areas of unmet need.
1. Improve the performance (including prognostic/predictive accuracy and coefficient of variance) of plasma
RNA biomarkers by more specifically measuring EV-RNAs on validated platforms in biorepository plasma
samples from carefully-phenotyped HF and post-MI patients.
2. Determine a functional role for EVs isolated from human HF samples with varied phenotypes in simplified
cell culture (iPSC-derived CMs) and organ-on-chip models
3. Leverage a novel murine model of exosome tracking (ExoMap) mouse to determine the functional
consequences of exosome targeting in cardiomyocytes and other cardiac cells in murine models of ischemic
and non-ischemic HF using single cell nuclear RNAseq.
4. Identify small molecule regulators of EV release/uptake to manipulate EV-mediated signaling in these
murine models.
5. Leverage newly identified cellular RNA biomarkers to develop novel conditional siRNA therapeutics that
target cardiac hypertrophy, autophagy and fibrosis.
The flexibility and latitude afforded by the R35 mechanism will allow me to pursue these high-risk high-reward
experiments that seek to address critical gaps in this field and will also provide time for devoting to mentoring
of the next generation of cardiovascular disease investigators.
尽管心力衰竭(HF)的治疗取得了重要进展,但仍有50%的患者在5年内死亡
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)
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Saumya Das其他文献
Saumya Das的其他文献
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{{ truncateString('Saumya Das', 18)}}的其他基金
Characterization of beta-cell-specific extracellular vesicle cargo as functional biomarkers for type I DM disease
β细胞特异性细胞外囊泡货物作为 I 型 DM 疾病功能性生物标志物的表征
- 批准号:
10517890 - 财政年份:2022
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Using ex vivo, in vivo models and patient mutations to interrogate pancreatic exocrine-endocrine cross talk
使用离体、体内模型和患者突变来探究胰腺外分泌-内分泌串扰
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Characterization of beta-cell-specific extracellular vesicle cargo as functional biomarkers for type I DM disease
β细胞特异性细胞外囊泡货物作为 I 型 DM 疾病功能性生物标志物的表征
- 批准号:
10706576 - 财政年份:2022
- 资助金额:
$ 96.07万 - 项目类别:
Functional role and therapeutic targeting of exosomes and extracellular RNA biomarkers in heart failure
外泌体和细胞外 RNA 生物标志物在心力衰竭中的功能作用和治疗靶向
- 批准号:
10417068 - 财政年份:2020
- 资助金额:
$ 96.07万 - 项目类别:
Functional role and therapeutic targeting of exosomes and extracellular RNA biomarkers in heart failure
外泌体和细胞外 RNA 生物标志物在心力衰竭中的功能作用和治疗靶向
- 批准号:
10176560 - 财政年份:2020
- 资助金额:
$ 96.07万 - 项目类别:
Functional role and therapeutic targeting of exosomes and extracellular RNA biomarkers in heart failure
外泌体和细胞外 RNA 生物标志物在心力衰竭中的功能作用和治疗靶向
- 批准号:
10630193 - 财政年份:2020
- 资助金额:
$ 96.07万 - 项目类别:
Molecular dissection and imaging of extracellular vesicles to define their origin and targets
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10350010 - 财政年份:2019
- 资助金额:
$ 96.07万 - 项目类别:
Molecular dissection and imaging of extracellular vesicles to define their origin and targets
细胞外囊泡的分子解剖和成像以确定其起源和目标
- 批准号:
9811730 - 财政年份:2019
- 资助金额:
$ 96.07万 - 项目类别:
Molecular dissection and imaging of extracellular vesicles to define their origin and targets
细胞外囊泡的分子解剖和成像以确定其起源和目标
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10018945 - 财政年份:2019
- 资助金额:
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