Surfactant Protein C Mouse Models: A Fit For Purpose Preclinical Platform For Advancing Discovery In And Treatment Of Idiopathic Pulmonary Fibrosis
表面活性剂蛋白 C 小鼠模型:一个适合目的的临床前平台,可促进特发性肺纤维化的发现和治疗
基本信息
- 批准号:10321882
- 负责人:
- 金额:$ 80.14万
- 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:2021-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAgeAgingAllelesAlveolarAnabolismArchitectureAutomobile DrivingAutophagocytosisBiological MarkersBronchoalveolar Lavage FluidCellsCellular StressCellular biologyCessation of lifeCharacteristicsChronicCicatrixClinicalCommunitiesComplicationCoupledDataDependenceDevelopmentDiseaseDisease ProgressionDistalElderlyElementsEpithelialEvolutionFibrosisFoundationsFunctional disorderGasesGene Expression ProfileGenerationsGenesGoalsGoldHandHigh Resolution Computed TomographyHistologyHumanImpairmentInjuryInterstitial Lung DiseasesInvestigationKnock-inKnock-in MouseLigandsLungLung TransplantationMapsMedicalMesenchymalModelingMorbidity - disease rateMusMutant Strains MiceMutationOrganellesOrganoidsOutcomePathogenesisPathway interactionsPatientsPatternPeripheralPhenotypePhysiologicalPhysiologyPirfenidonePopulationPre-Clinical ModelProcessProtein IsoformsProteomicsPublished CommentPublishingPulmonary FibrosisPulmonary Surfactant-Associated Protein CQuality ControlRefractoryReportingResearchResourcesRespiratory FailureSamplingSerumSignal PathwayStressStructure of parenchyma of lungSyndromeTestingTherapeuticTimeUsual Interstitial PneumoniaValidationWorkagedalveolar epitheliumbasebiobankcandidate markercohortendoplasmic reticulum stressfibrogenesisfibrotic lunggenetic varianthigh resolution imagingidiopathic pulmonary fibrosisin vivoinduced pluripotent stem cellinjury and repairinsightlung repairmortalitymouse modelmutantnew therapeutic targetnintedanibnon-Nativenovelnovel therapeuticspre-clinicalprimary endpointprogramsradiological imagingreceptorresponsesecondary endpointsexsingle-cell RNA sequencingtherapeutic developmenttherapy outcometraffickingtranscriptomicsvalidation studieswound healing
项目摘要
ABSTRACT
Idiopathic Pulmonary fibrosis (IPF) is a devastating interstitial lung disease (ILD) of older adults characterized
by disruption of distal lung architecture that ultimately leads to scar formation, abnormal gas exchange, and
respiratory failure. A key barrier to developing better therapeutic outcomes for IPF has been a dearth of
translationally relevant preclinical models. Based on a recent paradigm shift wherein the concepts of repetitive
injury to a dysfunctional, vulnerable, alveolar epithelium coupled with an abnormal wound healing response are
postulated as disease “drivers”, new opportunities are emerging for therapeutic discovery in IPF. Mutations in
the alveolar type 2 cell (AT2) restricted, Surfactant Protein C [SP-C] gene [SFTPC], have been found in
sporadic and familial IPF and provide important clues for understanding IPF pathogenesis. To address the
unmet need for IPF patients, this proposal builds upon on a strong foundation of our prior work characterizing
the cell biology of SP-C biosynthesis that culminated in generation of two novel knock-in mouse models of
spontaneous lung fibrosis already in hand which express clinical SP-C mutants in AT2 cells in an allelic and
inducible fashion. Our Published Data has demonstrated that clinical IPF associated SFTPC mutations
produce aberrant SP-C proprotein isoforms that functionally segregate into 2 AT2 phenotypes: ER stress
induced by intracellular SP-C misfolding (BRICHOS) or autophagy/mitophagy impaired from proSP-C
mistrafficking to non-native organelles (Non-BRICHOS). When expressed in the lung epithelium in vivo, both
the non-BRICHOS mutant (SftpcI73T) and the BRICHOS mutant (SftpcC121G) are extremely toxic to the lung and
each is sufficient to evoke a time-dependent, physiologically restrictive peripheral fibrotic lung phenotype that
elaborates translationally relevant biomarkers reported in human IPF. This proposal will leverage these unique
models for Discovery, Target ID/ Validation, and Proof of Concept studies aimed at mapping cell
subpopulations and uncovering novel pathways driving lung fibrosis whilst providing a compelling translational
platform to interface with other preclinical/translational platforms in this U01 consortium to accelerate IPF
therapeutic development. In 3 specific aims, we propose to utilize Sftpc mutant mice to map cell populations,
transcriptomic profiles, and cell-cell crosstalk repertoires arising during evolution of spontaneous fibrotic lung
phenotypes [Specific Aim 1], identify novel disease relevant biomarker candidates elaborated during the
aberrant injury-repair process [Specific Aim 2], and assess the important contributions of and mechanisms by
which aging and sex impact IPF phenotypes [Specific Aim 3]. Importantly, many of the endpoints defined in
Sftpc models will be cross-validated and contextualized using lung tissue and serum from a well-phenotyped
human IPF biorepository. When completed, the impactful deliverables produced from this project will include a
new platform to better understand IPF pathogenesis from its onset through disease progression and serve as a
resource for the broader research community to identify and test novel therapies to treat this disease.
摘要
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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MICHAEL FRANCIS BEERS其他文献
MICHAEL FRANCIS BEERS的其他文献
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{{ truncateString('MICHAEL FRANCIS BEERS', 18)}}的其他基金
COVID-19: Understanding The Role of Corona Virus InducedDisruption Of Alveolar Type 2 Cell Function And SurfactantHomeostasis In The Pathogenesis Of COVID-19 AcuteRespiratory Distress Syndrome
COVID-19:了解冠状病毒引起的肺泡 2 型细胞功能和表面活性剂稳态破坏在 COVID-19 急性呼吸窘迫综合征发病机制中的作用
- 批准号:
10744174 - 财政年份:2021
- 资助金额:
$ 80.14万 - 项目类别:
Surfactant Protein C Mouse Models: A Fit For Purpose Preclinical Platform For Advancing Discovery In And Treatment Of Idiopathic Pulmonary Fibrosis
表面活性剂蛋白 C 小鼠模型:一个适合目的的临床前平台,可促进特发性肺纤维化的发现和治疗
- 批准号:
10542732 - 财政年份:2021
- 资助金额:
$ 80.14万 - 项目类别:
COVID-19: Understanding The Role of Corona Virus InducedDisruption Of Alveolar Type 2 Cell Function And SurfactantHomeostasis In The Pathogenesis Of COVID-19 AcuteRespiratory Distress Syndrome
COVID-19:了解冠状病毒引起的肺泡 2 型细胞功能和表面活性剂稳态破坏在 COVID-19 急性呼吸窘迫综合征发病机制中的作用
- 批准号:
10152248 - 财政年份:2021
- 资助金额:
$ 80.14万 - 项目类别:
Surfactant Protein C Mouse Models: A Fit For Purpose Preclinical Platform For Advancing Discovery In And Treatment Of Idiopathic Pulmonary Fibrosis
表面活性剂蛋白 C 小鼠模型:一个适合目的的临床前平台,可促进特发性肺纤维化的发现和治疗
- 批准号:
10025851 - 财政年份:2021
- 资助金额:
$ 80.14万 - 项目类别:
COVID-19: Understanding The Role of Corona Virus InducedDisruption Of Alveolar Type 2 Cell Function And SurfactantHomeostasis In The Pathogenesis Of COVID-19 AcuteRespiratory Distress Syndrome
COVID-19:了解冠状病毒引起的肺泡 2 型细胞功能和表面活性剂稳态破坏在 COVID-19 急性呼吸窘迫综合征发病机制中的作用
- 批准号:
10367948 - 财政年份:2021
- 资助金额:
$ 80.14万 - 项目类别:
Alveolar Epithelial Cell Dysfunction in Pulmonary Fibrosis: Leveraging SFTPC Mutations for Discovery of Molecular and Cellular Targets
肺纤维化中的肺泡上皮细胞功能障碍:利用 SFTPC 突变发现分子和细胞靶点
- 批准号:
10165806 - 财政年份:2019
- 资助金额:
$ 80.14万 - 项目类别:
Alveolar Epithelial Cell Dysfunction in Pulmonary Fibrosis: Leveraging SFTPC Mutations for Discovery of Molecular and Cellular Targets
肺纤维化中的肺泡上皮细胞功能障碍:利用 SFTPC 突变发现分子和细胞靶点
- 批准号:
10407546 - 财政年份:2019
- 资助金额:
$ 80.14万 - 项目类别:
Biosynthesis and Trafficking of Surfactant Protein C In Health and Disease
表面活性剂蛋白 C 在健康和疾病中的生物合成和运输
- 批准号:
8559147 - 财政年份:2013
- 资助金额:
$ 80.14万 - 项目类别:
Biosynthesis and Trafficking of Surfactant Protein C In Health and Disease
表面活性剂蛋白 C 在健康和疾病中的生物合成和运输
- 批准号:
8731968 - 财政年份:2013
- 资助金额:
$ 80.14万 - 项目类别:
Biosynthesis and Trafficking of Surfactant Protein C In Health and Disease
表面活性剂蛋白 C 在健康和疾病中的生物合成和运输
- 批准号:
9281865 - 财政年份:2013
- 资助金额:
$ 80.14万 - 项目类别:
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