Protein inhibitor of galectin-3 to limit fibrosis after myocardial infarction

Galectin-3 蛋白抑制剂可限制心肌梗死后纤维化

基本信息

  • 批准号:
    8597803
  • 负责人:
  • 金额:
    $ 30万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-09-04 至 2014-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The wound-healing response of the human body to injuries involves induction of fibrosis, which is a dynamic scarring process. When fibrosis occurs in internal organs, it is indisputably a major cause of morbidity and mortality worldwide. The overall goal of the proposed research is to develop an inhibitor of galectin-3 as a drug that will limit excess fibrosis and adverse remodeling of the heart after myocardial infarction (heart attack) and, thereby, improve patient outcomes and reduce mortality. In the Phase I project, we will test the feasibility of using a dominant-negative galectin-3 inhibitor, termed galectin-3C (Ga-3C), to limit adverse remodeling and improve cardiac function after myocardial infarction (MI). MI is the most common cause of cardiac morbidity and mortality in the western world, and is responsible for 1 in 6 deaths (~400,000) in the US per year. Galectin- 3 is one of the galectin family of lectins that has homologous carbohydrate recognition domains and characteristic affinity for ¿-galactosides. There are compelling in vitro and animal data showing that galectin-3 is critical for organ fibrosis and specifically fibrosis in the heart. In humans, plasma levels of galectin-3 are approved by the US FDA and in Europe as a biomarker for risk of mortality in those with chronic heart failure (www.galectin-3.com) that is independent of severity of heart failure or renal dysfunction. The Phase I Specific Aims are as follows: 1. To determine the effect of Gal-3C on the TGF- ¿1-induced differentiation of primary cardiac fibroblasts to myofibroblasts and on their resulting collagen secretion. 2. To determine an effective dose of Gal-3C to reduce fibrosis in a rat ischemia/reperfusion model of MI. Subaim 2A. We will perform an initial dose-range finding study using osmotic pumps to deliver Gal-3C to rats after surgical induction of MI. Levels of collagen in the heart wil be analyzed as the main endpoint. Subaim 2B. We will test two different doses of Gal-3C administered over days 1-7 post-MI to determine its effect on 1 month post-MI cardiac function. 3. To determine if immediate or delayed treatment with Gal-3C leads to better cardiac function. Subaim 3A. We will assay serum collected at different times from the rats in Subaim 2B to establish the time-course of galectin-3 appearance, to determine the time window for Gal-3C delivery. Subaim 3B. We will repeat the Gal-3C delivery experiment from Aim 2 with delayed treatment timing based on what we learn in Subaim 3A. In Phase II, we plan to test a sustained-release form or a Gal-3C construct with a longer circulating half-life, conduct studies to refine post-MI treatment in animal models, and focus on toxicology, pharmacokinetics, and GMP production towards filing an IND application with the FDA and initiation of Phase I human clinical trials.
描述(由申请人提供):人体对损伤的创面愈合反应涉及到纤维化的诱导,这是一个动态的瘢痕形成过程。当纤维化发生在内脏器官时,它是无可争议的世界范围内发病率和死亡率的主要原因。拟议研究的总体目标是开发一种半乳糖凝集素-3抑制剂,作为一种药物,可以限制心肌梗死(心脏病发作)后过度纤维化和心脏不良重构,从而改善患者预后并降低死亡率。在一期项目中,我们将测试使用一种优势阴性半乳糖凝集素-3抑制剂的可行性,称为半乳糖凝集素- 3c (Ga-3C),以限制心肌梗死(MI)后的不良重塑和改善心功能。心肌梗死是西方世界心脏发病和死亡的最常见原因,在美国每年有六分之一的死亡(约40万人)是心肌梗死造成的。凝集素- 3是凝集素家族中的一员,具有同源碳水化合物识别结构域和对-半乳糖苷的特征亲和力。有令人信服的体外和动物数据表明半乳糖凝集素-3对器官纤维化,特别是心脏纤维化至关重要。在人类中,血浆半乳糖凝集素-3水平已被美国FDA和欧洲批准作为慢性心力衰竭患者死亡风险的生物标志物(www.galectin-3.com),与心力衰竭或肾功能不全的严重程度无关。第一阶段的具体目标如下:

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(2)

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Constance M John其他文献

SPINAL EXPRESSION OF NEUROTROPHIN-3 PREVENTS MUSCULAR CHANGES OF THE URINARY BLADDER AFTER SPINAL CORD CONTUSION IN RATS
  • DOI:
    10.1016/s0022-5347(08)61027-7
  • 发表时间:
    2008-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Thomas M Fandel;Linda J Noble-Haeusslein;Alpa A Mahuvakar;Constance M John;Tom F Lue;Emil A Tanagho
  • 通讯作者:
    Emil A Tanagho

Constance M John的其他文献

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{{ truncateString('Constance M John', 18)}}的其他基金

Inhibition of Galectin-3 for Therapy of Remodeling After Myocardial Infarction
半乳糖凝集素3抑制治疗心肌梗死后重构
  • 批准号:
    9202835
  • 财政年份:
    2016
  • 资助金额:
    $ 30万
  • 项目类别:
Inhibition of Galectin-3 for Therapy of Remodeling After Myocardial Infarction
半乳糖凝集素3抑制治疗心肌梗死后重构
  • 批准号:
    9453176
  • 财政年份:
    2016
  • 资助金额:
    $ 30万
  • 项目类别:
Model of the Human Testis for Reproductive Toxicology
用于生殖毒理学的人类睾丸模型
  • 批准号:
    8201518
  • 财政年份:
    2011
  • 资助金额:
    $ 30万
  • 项目类别:
Human Sertoli Cell Model for Study of Male Reproductive Function and Toxicity
用于研究男性生殖功能和毒性的人类支持细胞模型
  • 批准号:
    7327186
  • 财政年份:
    2007
  • 资助金额:
    $ 30万
  • 项目类别:
Novel biomarkers for neuronal damage in multiple sclerosis
多发性硬化症神经元损伤的新型生物标志物
  • 批准号:
    7053269
  • 财政年份:
    2006
  • 资助金额:
    $ 30万
  • 项目类别:
Novel Treatment for Breast Cancer: Truncated Galectin-3
乳腺癌的新疗法:截短的半乳糖凝集素 3
  • 批准号:
    6489447
  • 财政年份:
    2001
  • 资助金额:
    $ 30万
  • 项目类别:
Novel Treatment for Breast Cancer: Truncated Galectin-3
乳腺癌的新疗法:截短的半乳糖凝集素 3
  • 批准号:
    6401370
  • 财政年份:
    2001
  • 资助金额:
    $ 30万
  • 项目类别:
PLACENTAL CELLS FOR PROTECTION OF IMPLANTED B ISLETS
用于保护植入 B 胰岛的胎盘细胞
  • 批准号:
    6352407
  • 财政年份:
    2000
  • 资助金额:
    $ 30万
  • 项目类别:
POLYATOMIC PRIMARY BEAM FOR SIMS
用于 SIMS 的多原子主光束
  • 批准号:
    3505405
  • 财政年份:
    1992
  • 资助金额:
    $ 30万
  • 项目类别:
MASS SPECTROMETRIC SURFACE ANALYSIS OF MEMBRANES
膜的质谱表面分析
  • 批准号:
    3498797
  • 财政年份:
    1992
  • 资助金额:
    $ 30万
  • 项目类别:
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