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Engineered Models of Diseased Heart Valves to Study Sex Bias in Disease Progression

患病心脏瓣膜的工程模型用于研究疾病进展中的性别偏见

基本信息

批准号：
10317066
负责人：
Bo Liu
金额：
$ 38.21万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10317066
关键词：
3-Dimensional Address Affect Age Animals Architecture Biological Biology Cardiovascular system Cells Characteristics Clinical Computer Models Controlled Environment Cues Data Disease Disease Progression Disease model Engineering Environment Etiology Event Exhibits Exposure to Extracellular Matrix Female Fibrosis Future Heart Valve Diseases Human Hyperlipidemia In Vitro Individual Infiltration Inflammation Intervention Investigation Ligands Measures Methods Modeling Molecular Monitor Organ Culture Techniques Outcome Pathogenesis Pathologic Pathway interactions Phenotype Physiological Prevalence Prevention Process Research Resistance Risk Factors Sclerosis Sex Bias Sex Differences Signal Pathway Smoking Stenosis Stimulus Surgical Valves Techniques Testing Tissue Engineering Tissues Woman Work aortic valve aortic valve disorder attenuation base calcification comorbidity density design disorder prevention disorder risk effective therapy experimental study high risk human old age (65+)improved interstitial cell macrophage male men mimetics novel novel strategies prospective response sex three dimensional structure tissue support frame tool valve replacement

项目摘要

PROJECT SUMMARY Calcific aortic valve disease (CAVD) is a prevalent condition for which the only approved treatment is surgical valve replacement. Age and male sex are the dominant risk factors for developing this disease, which is characterized in its earliest stages by a change in extracellular matrix (ECM) composition. Moreover, recent evidence has indicated that the pathogenesis of CAVD in men may differ from that in women. We hypothesize that male and female valvular cells exhibit differential responsiveness to their microenvironment (i.e., ECM) and pathological cues (i.e., co-morbidities or risk factors), resulting in divergent disease trajectories for men and women. While clinical and animal studies can provide snapshots of disease progression, they do not permit the tailorability and high throughput needed to investigate this question and precisely monitor the specific cell/microenvironment/stimulus interactions that may yield mechanistic information about disease progression. Thus, we propose to develop in vitro disease-mimicking environments. Specifically, we will use novel tissue engineering and ECM-editing methods to create 3D engineered environments that recapitulate key features of the valve ECM and valvular interstitial cell phenotype at various stages of CAVD, and then use these scaffolds/tissues to examine disease progression upon exposure to risk factors and pathological stimuli. These defined, controlled environments will enable hypothesis testing that is impossible in humans and very difficult or not practical in animals, and will allow a prospective etiological investigation of sex bias in events that contribute to CAVD through execution of the following Aims: Aim 1: Construct engineered models that represent the valve microenvironment at different stages of disease. Aim 2: Investigate sex bias in the onset of inflammation using engineered models of CAVD. Aim 3: Investigate sex bias in the progression of fibrosis using engineered models of CAVD. Aim 4: Design organ cultures to validate engineered disease models and probe mechanism. This work has the potential to identify specific valve changes that can inform the design of sex- or stage- specific intervention strategies to reduce CAVD risk or progression and sets the stage for future work to improve CAVD prevention and treatment. We will make these advancements through our implementation of transformative approaches and tools to study ECM (patho)biology, which can also be readily applied to other cardiovascular (or non-cardiovascular tissues).

项目总结钙化性主动脉瓣病(Cavd)是一种流行的疾病，唯一被批准的治疗方法是外科手术。瓣膜置换。年龄和男性是罹患这种疾病的主要危险因素。以细胞外基质(ECM)组成变化为特征的早期阶段。此外，最近有证据表明，男性CAVD的发病机制可能与女性不同。我们假设男性和女性瓣膜细胞对它们的微环境(即ECM)和病理线索(即共病或风险因素)，导致分歧男性和女性的疾病轨迹。虽然临床和动物研究可以提供疾病的快照进展，它们不允许研究这个问题所需的可裁剪性和高吞吐量，并且精确监控特定的细胞/微环境/刺激相互作用，可能会产生机械性有关疾病进展的信息。因此，我们建议开发体外模拟疾病的环境。具体地说，我们将使用新的组织工程学和ECM编辑方法来创建3D工程化总结不同瓣膜ECM和瓣膜间质细胞表型的主要特征的环境 CAVD的分期，然后使用这些支架/组织来检查暴露于风险中的疾病进展因素和病理刺激。这些定义的、受控的环境将使假设检验成为可能在人类中是不可能的，在动物中非常困难或不实用，并将允许预期的病因学通过执行以下目标，调查导致CAVD的事件中的性别偏见：目的1：构建代表疾病不同阶段瓣膜微环境的工程化模型。目的2：利用CAVD工程化模型研究炎症发生中的性别偏见。目的3：利用CAVD的工程化模型研究纤维化进展中的性别偏见。目的4：设计器官培养以验证工程化疾病模型和探测机制。这项工作有可能识别特定的瓣膜变化，从而为性别或阶段的设计提供信息。降低CAVD风险或进展的具体干预策略，并为未来的工作奠定基础提高心脑血管疾病防治水平。我们将通过实施研究ECM(病理)生物学的变革性方法和工具，也可以很容易地应用于其他心血管(或非心血管组织)。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ten simple rules for women principal investigators during a pandemic.

DOI：
10.1371/journal.pcbi.1008370
发表时间：
2020-10
期刊：
PLoS computational biology
影响因子：
4.3
作者：
Kreeger PK;Brock A;Gibbs HC;Grande-Allen KJ;Huang AH;Masters KS;Rangamani P;Reagan MR;Servoss SL
通讯作者：
Servoss SL

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