课题基金 / 基金详情

Marfan Aortic Embryologic Origin Influences Aneurysm Formation

Marfan Aortic Embryologic Origin Influences Aneurysm Formation
马凡主动脉胚胎起源影响动脉瘤的形成
批准号:
10366102
负责人:
Michael Peter Fischbein
金额:
$65.46万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
未结题
起止时间:
2016-04-01 至 2026-03-31

项目摘要

项目成果

Michael Peter Fischbein的其他基金

相似基金

相关文献

中文摘要
翻译
项目摘要 马凡氏综合征(MFS)是由MFS-1基因突变引起的,是最常见的遗传性结缔组织疾病。 组织紊乱患者通常会发展为主动脉根部动脉瘤,随后发生主动脉夹层和破裂 仍然是导致死亡的主要原因。如果不进行预防性手术,预期寿命将减少到40岁。 新的靶向药物治疗一直缺乏,可能是由于机制理解的局限性。因此,在本发明中, 迫切需要研究MFS主动脉壁细胞外基质(ECM)参与的途径, 破裂导致动脉瘤形成。我们假设不同的胚胎来源的平滑肌细胞, 主动脉根有助于主动脉根特异性动脉瘤病理生理学。在最近的融资期内,我们 从MFS患者中创建并表征诱导多能干细胞(iPSC),并将其分化为 来自每个胚胎来源的SMC。我们了解到,microRNA、miR-29 b和相关下游基因 依赖于SMC的胚胎起源。在应用高通量蛋白质组学之后,我们还发现, 来自MFS患者的iPSC衍生的SMC表达不同的谱系特异性蛋白质组学谱,其影响关键的 生物学过程包括ECM合成/变性和SMC收缩/运动。利用单细胞RNA 测序,我们确定了一个独特的,疾病特异性SMC簇,发展转录组学改变 在鼠模型和人主动脉根部动脉瘤中区域性地。在赠送的MFS Fbn 1C 1041 G/+鼠标中 在体内研究中,我们发现了几个区域性上游TGF-β依赖性触发因子, 基质金属蛋白酶介导的ECM重塑,包括:(a)Ras(GTdR)信号传导;(B)NADPH 活化导致活性氧产生;和(c)雄激素增强TGF-β信号传导, 雄性老鼠药物阻断每一个发现的途径减少动脉瘤的形成。 在这次更新申请中,我们通过提出几项创新性的建议来严格扩展我们的研究进展。 为了研究SMC谱系对局部ECM重塑的相对贡献,研究了SMC谱系对局部ECM重塑的影响。 动脉瘤形成过程中调制SMC的上游触发和病理作用,并推进 翻译疾病特异性iPSC建模用于新途径发现。具体目标1: MFS SHF-和神经嵴-SMC之间的相互作用诱导合成SMC表型和ECM重塑。 我们研究了减少的SHF-SMC甘露糖受体2(MRC 2)对ECM组成的新作用, 蛋白水解和SMC收缩功能。我们还将阐明ECM生物力学特性对 谱系特异性SMC反应,包括SMC转录组调节和单细胞机械 特性.具体目标2致力于确定调节的SMC群体对ECM重塑的影响, 使用我们创新的MFS脱细胞基质支架进行体外培养。新的谱系追踪转基因小鼠模型 将用于识别调节的SMC胚胎起源和在体内动脉瘤进展中的作用。
英文摘要
PROJECT SUMMARY Marfan syndrome (MFS), caused by mutations in the fibrillin-1 gene, is the most common inherited connective tissue disorder. Patients typically develop aortic root aneurysms with ensuing aortic dissection and rupture remaining the leading cause of death. Without prophylactic surgery, life-expectancy is reduced to age 40 years. Novel targeted drug therapies have been absent, likely due to limitations in mechanistic understanding. Thus, there is an urgent need to dissect the pathway(s) involved in MFS aortic wall extracellular matrix (ECM) breakdown resulting in aneurysm formation. We hypothesize that distinct embryonic origins of SMCs populating the aortic root contribute to aortic root-specific aneurysm pathophysiology. In the recent funding period, we created and characterized induced-pluripotent stem cells (iPSCs) from MFS patients and differentiated them into SMCs from each embryologic origin. We learned that the microRNA, miR-29b and related downstream genes were dependent on SMC embryologic origin. After applying high-throughput proteomics, we also discovered that iPSC-derived SMCs from MFS patients express distinct, lineage-specific proteomic profiles affecting critical biologic processes including ECM synthesis/degeneration and SMC contraction/motility. Utilizing single-cell RNA sequencing, we identified a distinct, disease-specific SMC cluster that develops transcriptomic alterations regionally in both murine models and human aortic root aneurysms. In complimentary MFS Fbn1C1041G/+ mouse in vivo studies, we discovered several regional upstream TGF-β-dependent triggers that ultimately increase matrix metalloproteinase-mediated ECM remodeling, including: (a) Ras (GTPase) signaling; (b) NADPH activation leading to reactive oxygen species production; and (c) androgen potentiation of TGF-β signaling in male mice. Drug blockade of each discovered pathway reduced aneurysm formation. In this renewal application, we rigorously expand our research progress by proposing several innovative experiments to study the relative contributions of SMC lineages to regional ECM remodeling, investigate the upstream triggers and pathologic role of modulated SMCs during aneurysm formation, and advance the translation of disease-specific iPSC modeling for novel pathway discovery. Specific Aim 1 seeks whether interactions between MFS SHF- and neural crest-SMCs induce synthetic SMC phenotype and ECM remodeling. We investigate the novel role of reduced SHF-SMC mannose receptor 2 (MRC2) on ECM composition, proteolysis and SMC contractile function. We will also elucidate the effect of ECM biomechanical properties on lineage-specific SMC responses, including SMC transcriptomic modulation and single cell mechanical properties. Specific Aim 2 strives to determine the effects of modulated SMC populations on ECM remodeling in vitro using our innovative MFS decellularized matrix scaffolds. Novel lineage-tracing transgenic mouse models will be utilized to identify modulated SMC embryologic origin and role in aneurysm progression in vivo.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
R38 Stanford Integrated Cardiovascular/Pulmonary Residency Research Training Program
  • 批准号:
    10565903
  • 项目类别:
  • 资助金额:
    $32.86万
  • 财政年份:
    2020
  • 负责人:
    Michael Peter Fischbein
  • 依托单位:
R38 Stanford Integrated Cardiovascular/Pulmonary Residency Research Training Program
  • 批准号:
    10358507
  • 项目类别:
  • 资助金额:
    $33.54万
  • 财政年份:
    2020
  • 负责人:
    Michael Peter Fischbein
  • 依托单位:
Marfan Aortic Embryologic Origin Influences miR-29b Regulators and Targets
  • 批准号:
    9912106
  • 项目类别:
  • 资助金额:
    $28.76万
  • 财政年份:
    2016
  • 负责人:
    Michael Peter Fischbein
  • 依托单位:
Marfan Aortic Embryologic Origin Influences Aneurysm Formation
  • 批准号:
    10551326
  • 项目类别:
  • 资助金额:
    $65.46万
  • 财政年份:
    2016
  • 负责人:
    Michael Peter Fischbein
  • 依托单位:
国内基金
海外基金
补阳还五汤通过AGE-RAGE通路调控脓毒症免疫失衡的机制与转化研究
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
  • 批准号:
    JCZRQN202500010
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2025
  • 负责人:
  • 依托单位:
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
  • 批准号:
    2025JJ70209
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2025
  • 负责人:
    雷芬芳
  • 依托单位:
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
  • 批准号:
    --
  • 项目类别:
    面上项目
  • 资助金额:
    --
  • 批准年份:
    2024
  • 负责人:
    万荣
  • 依托单位: