Microfibril Fragments: Biomarkers of Aortic Disease

微纤维碎片:主动脉疾病的生物标志物

基本信息

  • 批准号:
    7835900
  • 负责人:
  • 金额:
    $ 47.41万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-09-30 至 2011-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Develop technologies for assessment of aortic aneurysms prone to rupture or dissection. Thoracic and abdominal aortic aneurysms (TAA and AAA) are life threatening conditions that comprise the thirteenth leading cause of death in the United States. For both TAAs and AAAs, monitoring the size of the aneurysm is the only determinant currently used to project the need for elective surgery and to avoid dissection or rupture. However, the size of the aneurysm is not a reliable predictor of aneurysms that are prone to rupture or dissection. Therefore, we propose to test whether circulating microfibril fragments can serve as biomarkers to profile the status and progression of aortic aneurysmal disease. We have already developed unique immunoassays (sandwich ELISAs) that can quantitate 4 fragments of fibrillin-1, 3 fragments of fibrillin-2, and 1 fragment of fibulin-4. These proteins are the major contributors to microfibril structure and function in the aortic elastic lamellae. Preliminary data demonstrate feasibility of using these assays to identify microfibril biomarker profiles for aortic aneurysms. Assays to measure other connective tissue protein fragments (e.g., the crosslinked telopeptides of collagen I and the endostatin domain of collagen XVIII) were based on the prior isolation of the fragments from serum or urine and the subsequent development of specific immunoassays. In contrast, our approach relies upon the exquisite specificities of monoclonal antibodies to detect fragments that are so far uncharacterized. Preliminary data indicate that this approach can identify novel biomarkers associated with Marfan syndrome (fibrillin-2 fragment 72-143) and aortic aneurysm (fibrillin-2 fragment 48-60) and can reveal signature biomarker profiles of aortic aneurysm (reduced fibrillin-1 fragments and increased fibrillin-2 fragments). We propose to use results from proposed studies of human and mouse Marfan syndrome as a wedge to gain insight into the mysteries of common types of aortic aneurysms. The Marfan syndrome, caused by mutations in the gene for fibrillin-1, is responsible for around 5% of all thoracic aortic aneurysms. With 1,100 plasma samples from individuals with aortic aneurysm (100 of these are Marfan), we will test the hypothesis that distinct fibrillin-1 and fibrillin-2 profiles, and possibly fibulin-4 profiles, will distinguish TAA from AAA. We will also use a new mouse model of Marfan syndrome to test whether profiles of circulating microfibril fragments can predict when aneurysms are prone to dissection and rupture and can monitor effects of treatment protocols to attenuate aortic disease progression. Results will quantitate threshold concentrations of circulating microfibril fragments required for dissection and rupture. If successful, our studies will greatly impact the medical management of aneurysmal disease and will lead to new research directions in this area. PUBLIC HEALTH RELEVANCE: For both thoracic and abdominal aneurysms, life threatening conditions, close monitoring of aneurysm size is the only way currently available to determine when to intervene with elective surgery or endovascular repair to avoid dissection or rupture. However, size is not a reliable predictor so new technologies are needed. We propose to meet this Challenge by testing whether circulating microfibril fragments can serve as biomarkers to reliably profile and monitor aneurysmal disease and identify aneurysms that are prone to dissection or rupture.
描述(由申请人提供):开发用于评估易破裂或夹层的主动脉瘤的技术。胸主动脉瘤和腹主动脉瘤(TAA和AAA)是威胁生命的疾病,在美国是第十三大死亡原因。对于TAA和AAA,监测动脉瘤的大小是目前用于预测择期手术需求和避免夹层或破裂的唯一决定因素。然而,动脉瘤的大小并不是容易破裂或夹层的动脉瘤的可靠预测因素。因此,我们建议测试循环微纤维片段是否可以作为生物标志物来描述主动脉粥样硬化疾病的状态和进展。我们已经开发了独特的免疫测定法(夹心ELISA),可以定量4个片段的微管蛋白-1,3个片段的微管蛋白-2,1个片段的fibulin-4。这些蛋白质是主动脉弹性膜中微纤维结构和功能的主要贡献者。初步数据证明了使用这些测定来鉴定主动脉瘤的微纤维生物标志物谱的可行性。测量其他结缔组织蛋白片段(例如,胶原蛋白I的交联端肽和胶原蛋白XVIII的内皮抑制素结构域)是基于先前从血清或尿中分离片段和随后开发特异性免疫测定。相比之下,我们的方法依赖于单克隆抗体的精确特异性来检测到目前为止尚未表征的片段。初步数据表明,这种方法可以鉴定与马凡氏综合征(Bcl 2 -2片段72-143)和主动脉瘤(Bcl 2 -2片段48-60)相关的新型生物标志物,并且可以揭示主动脉瘤的特征生物标志物谱(Bcl 2 -1片段减少和Bcl 2 -2片段增加)。我们建议使用人类和小鼠马凡氏综合征的研究结果作为一个楔子,以深入了解常见类型的主动脉瘤的奥秘。马凡氏综合征是由Thr-1基因突变引起的,约占所有胸主动脉瘤的5%。我们将使用来自主动脉瘤患者的1,100份血浆样本(其中100份为马凡氏动脉瘤),检验以下假设,即不同的β 1蛋白-1和β 2蛋白谱,以及可能的fibulin-4谱,将区分TAA和AAA。我们还将使用一种新的马凡氏综合征小鼠模型来测试循环微纤维碎片的特征是否可以预测动脉瘤何时容易夹层和破裂,并可以监测治疗方案对减缓主动脉疾病进展的影响。结果将定量剥离和破裂所需的循环微原纤维片段的阈值浓度。如果成功的话,我们的研究将极大地影响疾病的医疗管理,并将导致在这一领域的新的研究方向。 公共卫生相关性:对于危及生命的胸动脉瘤和腹动脉瘤,密切监测动脉瘤尺寸是目前唯一可用的方法,以确定何时进行择期手术或腔内修复术干预,以避免夹层或破裂。然而,规模并不是一个可靠的预测因素,因此需要新的技术。我们建议通过测试循环微纤维片段是否可以作为生物标志物来可靠地描述和监测动脉瘤疾病并识别易于发生动脉瘤的动脉瘤来应对这一挑战。 夹层或破裂。

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 }}

LYNN Y SAKAI其他文献

LYNN Y SAKAI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('LYNN Y SAKAI', 18)}}的其他基金

Musculoskeletal growth and homeostasis: does extracellular fibrillin matrix regulate Notch signaling components?
肌肉骨骼生长和稳态:细胞外原纤维蛋白基质是否调节 Notch 信号传导成分?
  • 批准号:
    10212242
  • 财政年份:
    2020
  • 资助金额:
    $ 47.41万
  • 项目类别:
Musculoskeletal growth and homeostasis: does extracellular fibrillin matrix regulate Notch signaling components?
肌肉骨骼生长和稳态:细胞外原纤维蛋白基质是否调节 Notch 信号传导成分?
  • 批准号:
    10057700
  • 财政年份:
    2020
  • 资助金额:
    $ 47.41万
  • 项目类别:
Translational Opportunities for the Heritable Disorders of Connective Tissue
结缔组织遗传性疾病的转化机会
  • 批准号:
    8205239
  • 财政年份:
    2011
  • 资助金额:
    $ 47.41万
  • 项目类别:
27th Annual Conference of the National Marfan Foundation
国家马凡基金会第27届年会
  • 批准号:
    8205409
  • 财政年份:
    2011
  • 资助金额:
    $ 47.41万
  • 项目类别:
Microfibril Fragments: Biomarkers of Aortic Disease
微纤维碎片:主动脉疾病的生物标志物
  • 批准号:
    7934626
  • 财政年份:
    2009
  • 资助金额:
    $ 47.41万
  • 项目类别:
PROJECT 2: MOLECULAR DISSECTION OF GROWTH FACTORS INVOLVED IN MFS (Lynn Y. Sakai,
项目 2:MFS 中涉及的生长因子的分子解剖(Lynn Y. Sakai,
  • 批准号:
    7460910
  • 财政年份:
    2007
  • 资助金额:
    $ 47.41万
  • 项目类别:
Imaging and Antibodies
成像和抗体
  • 批准号:
    7460913
  • 财政年份:
    2007
  • 资助金额:
    $ 47.41万
  • 项目类别:
6th Pan Pacific Connective Tissue Societies Symposium
第六届泛太平洋结缔组织学会研讨会
  • 批准号:
    7005359
  • 财政年份:
    2005
  • 资助金额:
    $ 47.41万
  • 项目类别:
Homeostasis and Repair in the Marfan Aorta
马凡主动脉的稳态和修复
  • 批准号:
    8122264
  • 财政年份:
    2004
  • 资助金额:
    $ 47.41万
  • 项目类别:
Homeostasis and Repair in the Marfan Aorta
马凡主动脉的稳态和修复
  • 批准号:
    8379272
  • 财政年份:
    2004
  • 资助金额:
    $ 47.41万
  • 项目类别:

相似海外基金

Establishment of human abdominal aortic aneurysm wall strength prediction model using Ex Vivo Superparamagnetic Iron Oxide–Enhanced Magnetic Resonance Imaging
利用Ex Vivo超顺磁性氧化铁建立人体腹主动脉瘤壁强度预测模型
  • 批准号:
    23K08226
  • 财政年份:
    2023
  • 资助金额:
    $ 47.41万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Vascular smooth muscle cell ferroptosis and abdominal aortic aneurysm
血管平滑肌细胞铁死亡与腹主动脉瘤
  • 批准号:
    10733477
  • 财政年份:
    2023
  • 资助金额:
    $ 47.41万
  • 项目类别:
Extracellular Vesicle Delivery System for Treatment of Abdominal Aortic Aneurysm
细胞外囊泡递送系统治疗腹主动脉瘤
  • 批准号:
    10751123
  • 财政年份:
    2023
  • 资助金额:
    $ 47.41万
  • 项目类别:
I-Corps: A Clinical Decision Support Tool to Manage Abdominal Aortic Aneurysm Patients
I-Corps:管理腹主动脉瘤患者的临床决策支持工具
  • 批准号:
    2318665
  • 财政年份:
    2023
  • 资助金额:
    $ 47.41万
  • 项目类别:
    Standard Grant
Atherosclerosis drives arterial damage and abdominal aortic aneurysm formation and rupture
动脉粥样硬化导致动脉损伤和腹主动脉瘤形成和破裂
  • 批准号:
    483212
  • 财政年份:
    2023
  • 资助金额:
    $ 47.41万
  • 项目类别:
    Operating Grants
Development of phospholipid-based nanotherapeutics for treating abdominal aortic aneurysm
开发基于磷脂的纳米疗法治疗腹主动脉瘤
  • 批准号:
    10749980
  • 财政年份:
    2023
  • 资助金额:
    $ 47.41万
  • 项目类别:
Impact of PCSK9 inhibition on abdominal aortic aneurysm pathobiology and growth
PCSK9 抑制对腹主动脉瘤病理学和生长的影响
  • 批准号:
    10566800
  • 财政年份:
    2023
  • 资助金额:
    $ 47.41万
  • 项目类别:
The Role of Amino Acid Starvation Response Kinase GCN2 in Abdominal Aortic Aneurysm
氨基酸饥饿反应激酶 GCN2 在腹主动脉瘤中的作用
  • 批准号:
    10584543
  • 财政年份:
    2022
  • 资助金额:
    $ 47.41万
  • 项目类别:
Atherosclerotic process drives arterial damage, abdominal aortic aneurysm formation, and rupture
动脉粥样硬化过程导致动脉损伤、腹主动脉瘤形成和破裂
  • 批准号:
    477264
  • 财政年份:
    2022
  • 资助金额:
    $ 47.41万
  • 项目类别:
    Operating Grants
Endovascular Orifice Detection (EOrD) Device for in situ Fenestration of Abdominal Aortic Aneurysm
用于腹主动脉瘤原位开窗的血管内孔口检测 (EOrD) 装置
  • 批准号:
    10453104
  • 财政年份:
    2022
  • 资助金额:
    $ 47.41万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了