Regulators of extracellular matrix production during cardiac development and disease

心脏发育和疾病过程中细胞外基质产生的调节因子

基本信息

  • 批准号:
    10241540
  • 负责人:
  • 金额:
    $ 40.5万
  • 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:
    2020-08-20 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

Cardiac fibrosis is a grim consequence for almost all myocardial injuries. In myocardial infarction (MI), what starts as a protective scarring process to prevent ventricular wall rupture becomes a pathological remodeling of the tissue with the accumulation of excess extracellular matrix (ECM) proteins. Eventually, this adaptation impedes the mechanical and electrical properties of the myocardium resulting in heart failure. Recently, we showed that periostin (Postn) expressing cells that arise from resident cardiac fibroblasts (CFs) are a potential therapeutic target since they differentiate into the scar associated, matrix-producing cell-type after MI injury. In fact, deletion of these cells after an acute MI injury eliminates interstitial fibrosis but results in ventricular rupture which is a hallmark outcome of impaired ECM deposition during the acute phase of MI. However, if we delete these cells during a chronic injury such as pressure overload-induced cardiac fibrosis model, we detect sustained perivascular fibrosis. Previous studies also report heterogeneity of origin and function for ECM-producing cells associated with different cardiac diseases. Consequently, our inability to identify cell- and state-specific therapeutic targets render cardiac fibrosis yet an incurable disease. Therefore, there is a critical need to determine the cellular composition and functional heterogeneity within ECM-producing fibroblasts. Until very recently, the main limitation has been the inability to accurately interrogate and manipulate the activities of different CF sub-populations differentiated from cells, including pericytes, endothelial cells, resident inflammatory cells in vivo given a lack of cell type-specific genetic tools. Recently, we and others have generated several novel genetic tools that now allow us to investigate all of the matrix-producing cells and their activated forms. Utilizing these new genetic tools in lineage tracing, gain-of-function, and loss-of-function studies, we will interrogate and determine the origin and function of all ECM-producing cell types as well as the molecular mechanisms that regulate CF sustained pathological activation and differentiation after acute or chronic disease models in mice. Our recent work where we effectively interrogated Postn expressing CF lineage in comparison to Postn negative CFs in a single-cell RNA sequencing analysis revealed distinct gene expression profiles between these two populations. Depending on the injury type, such as hearts subjected to MI, TAC, or Angiotensin induced fibrosis, we observed differences in ECM components as well as cellular composition. Finally, our preliminary data showed here identify another cell lineage that involves perivascular fibrosis. Therefore, we hypothesize that pathological ECM deposition resulting in fibrosis comes from disease-specific specialized sub-populations of CFs with distinct gene expressions. The following aims will rigorously interrogate CF subpopulations and the molecular mechanisms that regulate CF activation and ECM composition.
心脏纤维化是几乎所有心肌损伤的严重后果。在心肌梗死(MI)中, 一开始是防止心室壁破裂的保护性瘢痕形成过程, 随着过量细胞外基质(ECM)蛋白的积累,组织重塑。最终,这 自适应阻碍心肌的机械和电特性,导致心力衰竭。 最近,我们发现,从常驻心脏成纤维细胞(CF)中产生的骨膜蛋白(Postn)表达细胞, 是潜在的治疗靶点,因为它们分化成瘢痕相关的基质产生细胞类型 心肌梗死后。事实上,急性心肌梗死损伤后这些细胞的缺失消除了间质纤维化,但导致心肌梗死。 心室破裂是心肌梗死急性期ECM沉积受损的标志性结果。 然而,如果我们在慢性损伤(如压力超负荷诱导的心脏纤维化)期间删除这些细胞, 在模型中,我们检测到持续的血管周围纤维化。以前的研究也报道了起源的异质性, 与不同心脏疾病相关的ECM产生细胞的功能。 因此,我们无法识别细胞和状态特异性治疗靶点, 但却是不治之症因此,迫切需要确定细胞组成和功能, 产生ECM的成纤维细胞内的异质性。直到最近,主要的限制一直是无法 准确地询问和操纵从细胞分化的不同CF亚群的活性, 包括周细胞、内皮细胞、缺乏细胞类型特异性的体内驻留炎性细胞, 基因工具最近,我们和其他人已经产生了几种新的遗传工具,现在可以让我们 研究所有的制造基质的细胞和它们的激活形式。利用这些新的基因工具, 谱系追踪,功能获得和功能丧失研究,我们将询问和确定起源, 所有ECM产生细胞类型的功能以及调节CF持续的分子机制 在小鼠急性或慢性疾病模型后的病理活化和分化。我们最近的工作 我们有效地询问了表达CF谱系的Postn与Postn阴性CF在单细胞中的比较, RNA测序分析揭示了这两个群体之间不同的基因表达谱。 根据损伤类型,如心肌梗死、TAC或血管紧张素诱导的纤维化, 观察到ECM组分以及细胞组成的差异。最后,我们的初步数据显示, 这里鉴定了另一种涉及血管周围纤维化细胞谱系。因此,我们假设 导致纤维化的病理性ECM沉积来自疾病特异性的特化亚群 具有不同基因表达的CF。以下目标将严格询问CF亚群和 调节CF活化和ECM组成的分子机制。

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 }}

Onur Kanisicak其他文献

Onur Kanisicak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('Onur Kanisicak', 18)}}的其他基金

Functional and mechanistic delineation of HuR-Wisp1 signaling on myofibroblast activity
HuR-Wisp1信号对肌成纤维细胞活性的功能和机制描述
  • 批准号:
    10736289
  • 财政年份:
    2023
  • 资助金额:
    $ 40.5万
  • 项目类别:
Regulators of extracellular matrix production during cardiac development and disease
心脏发育和疾病过程中细胞外基质产生的调节因子
  • 批准号:
    10656462
  • 财政年份:
    2020
  • 资助金额:
    $ 40.5万
  • 项目类别:
Regulators of extracellular matrix production during cardiac development and disease
心脏发育和疾病过程中细胞外基质产生的调节因子
  • 批准号:
    10052792
  • 财政年份:
    2020
  • 资助金额:
    $ 40.5万
  • 项目类别:

相似海外基金

Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
  • 批准号:
    MR/X02329X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 40.5万
  • 项目类别:
    Fellowship
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
  • 批准号:
    MR/Y009568/1
  • 财政年份:
    2024
  • 资助金额:
    $ 40.5万
  • 项目类别:
    Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
  • 批准号:
    10090332
  • 财政年份:
    2024
  • 资助金额:
    $ 40.5万
  • 项目类别:
    Collaborative R&D
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
  • 批准号:
    MR/X021882/1
  • 财政年份:
    2024
  • 资助金额:
    $ 40.5万
  • 项目类别:
    Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
  • 批准号:
    MR/X029557/1
  • 财政年份:
    2024
  • 资助金额:
    $ 40.5万
  • 项目类别:
    Research Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
  • 批准号:
    EP/Y003527/1
  • 财政年份:
    2024
  • 资助金额:
    $ 40.5万
  • 项目类别:
    Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
  • 批准号:
    EP/Y030338/1
  • 财政年份:
    2024
  • 资助金额:
    $ 40.5万
  • 项目类别:
    Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
  • 批准号:
    2312694
  • 财政年份:
    2024
  • 资助金额:
    $ 40.5万
  • 项目类别:
    Standard Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
  • 批准号:
    24K19395
  • 财政年份:
    2024
  • 资助金额:
    $ 40.5万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Collaborative Research: Changes and Impact of Right Ventricle Viscoelasticity Under Acute Stress and Chronic Pulmonary Hypertension
合作研究:急性应激和慢性肺动脉高压下右心室粘弹性的变化和影响
  • 批准号:
    2244994
  • 财政年份:
    2023
  • 资助金额:
    $ 40.5万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了