Targeting Bcl-2 Family Proteins to Facilitate Fibroblast Apoptosis and Promote the Resolution of Pulmonary Fibrosis
靶向Bcl-2家族蛋白促进成纤维细胞凋亡并促进肺纤维化消退
基本信息
- 批准号:10701452
- 负责人:
- 金额:$ 0.25万
- 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:2021-06-09 至 2022-06-08
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAftercareApoptosisApoptoticAutoimmune DiseasesAutomobile DrivingBCL2 geneBehaviorBleomycinCellsCicatrixClinicalCollagenContractsDataDental CareDepositionDevelopmentDiseaseEffector CellEvaluationExposure toExtracellular MatrixFamilyFamily memberFibroblastsFibrosisFlow CytometryFundingGoldGrantHealthHistologyHumanHydroxyprolineIn VitroInduction of ApoptosisInfectionLaboratoriesLife ExpectancyLungLung diseasesMalignant NeoplasmsManuscriptsMeasuresMentorsMethodsMiningModelingMusNatural GasOccupationalOccupational ExposureOralOutcomePathologicPathway interactionsPatientsPharmaceutical PreparationsPharmacologyPhysiciansPreparationProcessPrognosisProtein FamilyProteinsPulmonary FibrosisReactionResistanceResolutionRisk FactorsRoleScientistSignal TransductionSilicon DioxideSilicosisSkinSmall Interfering RNASouth AfricaStructureTamoxifenTechniquesTestingTherapeuticTherapeutic InterventionTissuesTomatoesTrainingUnited StatesWorkcareerclinically relevantcollaborative environmentcrystallinityfibrotic lungfibrotic lung diseasefollower of religion Jewishhydraulic fracturingidiopathic pulmonary fibrosisimprovedin vivo Modelinducible gene expressionknock-downmicroCTmouse modelpreventprofibrotic fibroblastpromoterred fluorescent proteinskillstargeted treatmenttherapeutic targetwound healing
项目摘要
Project Summary/Abstract
This project aims to understand and control the anti-apoptotic mechanisms employed by fibroblasts to evade
apoptosis during the fibrotic process. Pulmonary fibrosis is a devastating disease affecting millions worldwide.
Profibrotic fibroblasts are key effector cells in fibrosis, which lay down collagen and can contract to deform
tissues. In normal wound healing, fibroblasts undergo apoptosis and are cleared, but in pathologic fibrotic
diseases fibroblast resistance to apoptosis allows them to persist and contribute to progressive and non-
resolving fibrosis. The intrinsic pathway of apoptosis is controlled by the Bcl-2 family of proteins. It is known that
in pulmonary fibrosis, fibroblasts have increased levels of the anti-apoptotic protein Bcl-2. However, there are
more than 15 Bcl-2 family members some of which are pro-apoptotic and some anti-apoptotic. Therefore,
understanding the apoptotic milieu of a cell requires more than simply measuring the levels of one Bcl-2 family
protein. In this proposal we will use cutting edge laboratory techniques to delineate the anti-apoptotic
strategy employed by profibrotic fibroblasts and leverage this behavior to induce fibroblast apoptosis
and resolution of pulmonary fibrosis. We will use primary lung fibroblasts cultured in vitro to explore the Bcl-
2 family interactions in fibroblasts using human and murine fibroblasts isolated from healthy and fibrotic lungs.
In Specific Aim 1, we will elucidate the Bcl-2 family protein levels, expression, and interactions in both the healthy
and fibrotic state, and determine if fibroblasts from fibrotic lungs are more resistant to intrinsic pathway driven
apoptosis. We will then evaluate the effects of inhibition and knockdown of anti-apoptotic proteins on fibroblast
apoptosis. In Specific Aim 2, we will use two in vivo models of persistent pulmonary fibrosis in mice (silica and
repetitive bleomycin) to explore the effects of Bcl-2 inhibition with the drug ABT-263 on fibroblast apoptosis and
pulmonary fibrosis. We will measure fibrosis with micro-CT, histology, and hydroxyproline levels. Using mice with
tamoxifen-inducible expression of the red fluorescent protein tomato under the control of the aSMA promoter,
we will track and quantify fibroblasts during and after treatment. Our work will provide a greater understanding
of anti-apoptotic mechanisms employed by fibroblasts and explore a viable therapeutic option to induce fibroblast
apoptosis. Our work will significantly add to our understanding of how the intrinsic pathway of apoptosis controls
the resolution and persistence of fibrosis and will potentially identify targets for therapeutic intervention.
My mentors and I have created a structured training plan that will provide training in the following domains:
question and hypothesis building, development of experimental approaches, basic and advanced cutting-edge
lab techniques, data evaluation and interpretation, data presentation and manuscript preparation, oral
presentation skills, and grant preparation and grantsmanship. This project will be carried out in the highly
collaborative environment at National Jewish Health, which serves as an outstanding platform on which to build
a career as an independently funded physician scientist.
项目总结/摘要
该项目旨在了解和控制成纤维细胞逃避凋亡的抗凋亡机制。
纤维化过程中的细胞凋亡。肺纤维化是一种毁灭性的疾病,影响着全世界数百万人。
促纤维化成纤维细胞是纤维化中的关键效应细胞,其沉积胶原并可收缩变形
组织中在正常的伤口愈合中,成纤维细胞经历凋亡并被清除,但在病理性纤维化中,
疾病成纤维细胞对细胞凋亡的抵抗使它们持续存在,并有助于进行性和非细胞性的细胞凋亡。
解决纤维化。细胞凋亡的内在途径由Bcl-2蛋白家族控制。已知的是
在肺纤维化中,成纤维细胞具有增加的抗凋亡蛋白Bcl-2水平。但有
超过15个Bcl-2家族成员,其中一些具有促细胞凋亡作用,一些具有抗细胞凋亡作用。因此,我们认为,
了解细胞的凋亡环境需要的不仅仅是测量一个Bcl-2家族的水平
蛋白在这项提案中,我们将使用最先进的实验室技术来描绘抗凋亡,
促纤维化成纤维细胞采用的策略,并利用这种行为诱导成纤维细胞凋亡
和肺纤维化的消退。我们将使用体外培养的原代肺成纤维细胞来探索Bcl-2的表达。
2使用从健康和纤维化肺分离的人和鼠成纤维细胞在成纤维细胞中的家族相互作用。
在具体目标1中,我们将阐明Bcl-2家族蛋白水平,表达和相互作用,在两个健康的人,
和纤维化状态,并确定来自纤维化肺的成纤维细胞是否对内源性途径驱动的
凋亡然后我们将评估抑制和敲低抗凋亡蛋白对成纤维细胞的影响。
凋亡在具体目标2中,我们将使用小鼠中持续性肺纤维化的两种体内模型(二氧化硅和
重复博来霉素)来探讨药物ABT-263抑制Bcl-2对成纤维细胞凋亡和
肺纤维化。我们将通过显微CT、组织学和羟脯氨酸水平来测量纤维化。使用小鼠,
在aSMA启动子控制下的红色荧光蛋白番茄的他莫昔芬诱导型表达,
我们将在治疗期间和治疗后跟踪和量化成纤维细胞。我们的工作将提供一个更好的理解
的抗凋亡机制,探索一种可行的治疗选择,诱导成纤维细胞
凋亡我们的工作将大大增加我们对细胞凋亡的内在途径如何控制
纤维化的解决和持续性,并将潜在地确定治疗干预的靶点。
我的导师和我已经制定了一个结构化的培训计划,将在以下领域提供培训:
问题和假设的建立,实验方法的发展,基础和先进的尖端
实验室技术,数据评估和解释,数据演示和手稿准备,口头
演讲技巧,以及赠款准备和赠款。该项目将在高度
国家犹太健康组织的协作环境,这是一个出色的平台,
作为一名独立资助的医学科学家。
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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Joseph Charles Cooley的其他文献
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{{ truncateString('Joseph Charles Cooley', 18)}}的其他基金
Targeting Bcl-2 Family Proteins to Facilitate Fibroblast Apoptosis and Promote the Resolution of Pulmonary Fibrosis
靶向Bcl-2家族蛋白促进成纤维细胞凋亡并促进肺纤维化消退
- 批准号:
10431774 - 财政年份:2021
- 资助金额:
$ 0.25万 - 项目类别:
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