Building a Better AMD Mouse

打造更好的 AMD 鼠标

基本信息

  • 批准号:
    7359744
  • 负责人:
  • 金额:
    $ 24.83万
  • 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:
    2009-08-01 至 2011-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a complex disease in which the contributions of many genetic and environmental factors are confounding. No single risk factor can predict AMD reliably in humans, and similarly, no single intervention in animals is able to produce a robust AMD model. The disease manifests as the more common dry form, and the less common, but more devastating wet form. Of the proposed mechanisms for dry AMD, most evidence exists for dysregulated systemic complement activation, predominantly due to polymorphisms in complement factor H, or CFH and a cardiovascular risk profile. The recent discovery of a polymorphic variant of HTRA Serine Peptidase 1 (HTRA1) as a risk factor for wet AMD implicates an entirely different mechanism (abnormal matrix metabolism and TGF-2 signaling) underlying the wet form of AMD. The ultimate intent of this proposal is to create an early onset, comprehensive AMD ocular phenotype in mice for future use in therapeutic trials. Our central hypothesis is that combining genetic and environmental risk factors can induce more comprehensive AMD-like pathology in mice. First, we will test the hypothesis that combined complement dysregulation and lipid-induced systemic inflammation can worsen AMD-like pathology. In Aim 1, we will breed mice lacking one or more genes conferring AMD risk in humans (CFH) or mice (ApoE, Ccr2) and expose these to normal or high fat high cholesterol diets. The effects of genotype and diet upon development of ocular pathology and biomarkers of inflammation will be compared. Next, we will explore the role of HTRA1 overexpression in wet AMD. In Aim 2, we will generate a Cre-Lox inducible HTRA1 knockin mouse that overexpresses human HTRA1 in a) endothelium or b) in the majority of tissues. This aim will test the hypothesis that HTRA1 overexpression can induce choroidal neovascularization typical of wet AMD. Experiments in Aim 1 will provide insight into whether complete CFH-/- deletion can result in AMD-like pathology when combined with additional genetic and dietary risk factors. In Aim 2, we will thoroughly test the hypothesis that increased expression of HTRA1 promotes CNV. The long term goal of this study is to combine the models developed in Aim1 and 2 to provide a comprehensive mouse model of progressive (i.e dry to wet) AMD in humans. Age-related macular degeneration is the predominant cause of vision loss in adults over 65. Lack of effective treatment stems from both the complexity of the disease, and lack of good animal models in which to study it. This proposal offers the potential to provide a robust early onset mouse model for therapeutic testing. These experiments also provide insight into how modifiable variables (diet) interact with predisposing genetic burden to create AMD pathology. Understanding these relationships will enhance the capacity of the clinician to council at-risk patients.
描述(由申请人提供):年龄相关性黄斑变性(AMD)是一种复杂的疾病,其中许多遗传和环境因素的贡献是混杂的。没有单一的风险因素可以可靠地预测人类的AMD,同样,没有单一的动物干预能够产生一个强大的AMD模型。该疾病表现为更常见的干型,以及不太常见但更具破坏性的湿型。在提出的干性AMD的机制中,大多数证据表明存在系统性补体激活失调,主要是由于补体因子H (CFH)的多态性和心血管风险概况。最近发现的HTRA丝氨酸肽酶1 (HTRA1)多态性变异是湿性AMD的一个危险因素,这暗示了湿性AMD的一个完全不同的机制(异常的基质代谢和TGF-2信号)。该提案的最终目的是在小鼠中创建一个早发性,全面的AMD眼部表型,用于未来的治疗试验。我们的中心假设是遗传和环境风险因素的结合可以在小鼠中诱导更全面的amd样病理。首先,我们将验证补体失调和脂质诱导的全身性炎症相结合会加重amd样病理的假设。在目标1中,我们将培养缺乏一种或多种人类(CFH)或小鼠(ApoE, Ccr2) AMD风险基因的小鼠,并将其暴露于正常或高脂肪高胆固醇饮食中。比较基因型和饮食对眼部病理发展和炎症生物标志物的影响。接下来,我们将探讨HTRA1过表达在湿性AMD中的作用。在Aim 2中,我们将生成Cre-Lox诱导的HTRA1敲入小鼠,该小鼠在a)内皮或b)大多数组织中过度表达人HTRA1。本研究旨在验证HTRA1过表达可诱导湿性AMD典型脉络膜新生血管形成的假设。Aim 1的实验将深入了解当与其他遗传和饮食风险因素结合时,完全的CFH-/-缺失是否会导致amd样病理。在Aim 2中,我们将彻底验证HTRA1表达增加促进CNV的假设。本研究的长期目标是将ai1和2中建立的模型结合起来,提供一个全面的人类进行性(即干性到湿性)AMD的小鼠模型。年龄相关性黄斑变性是65岁以上成年人视力丧失的主要原因。缺乏有效的治疗源于疾病的复杂性,以及缺乏良好的动物模型来研究它。这一建议为治疗试验提供了一个强大的早期发病小鼠模型。这些实验还提供了可改变变量(饮食)如何与易感遗传负担相互作用以产生AMD病理的见解。了解这些关系将提高临床医生对高危患者进行咨询的能力。

项目成果

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Caroline J Zeiss其他文献

Caroline J Zeiss的其他文献

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{{ truncateString('Caroline J Zeiss', 18)}}的其他基金

SARS-CoV-2 and Influenza Infection in the Syrian Hamster
叙利亚仓鼠的 SARS-CoV-2 和流感感染
  • 批准号:
    10175735
  • 财政年份:
    2020
  • 资助金额:
    $ 24.83万
  • 项目类别:
Complex Mouse Models of Age-related Macular Degeneration
年龄相关性黄斑变性的复杂小鼠模型
  • 批准号:
    8044952
  • 财政年份:
    2011
  • 资助金额:
    $ 24.83万
  • 项目类别:
Complex Mouse Models of Age-related Macular Degeneration
年龄相关性黄斑变性的复杂小鼠模型
  • 批准号:
    8213396
  • 财政年份:
    2011
  • 资助金额:
    $ 24.83万
  • 项目类别:
Building a Better AMD Mouse
打造更好的 AMD 鼠标
  • 批准号:
    7895547
  • 财政年份:
    2009
  • 资助金额:
    $ 24.83万
  • 项目类别:
MICROARRAY ANALYSIS OF RETINAL DEGENERATION IN MICE
小鼠视网膜变性的微阵列分析
  • 批准号:
    6612234
  • 财政年份:
    2003
  • 资助金额:
    $ 24.83万
  • 项目类别:
MICROARRAY ANALYSIS OF RETINAL DEGENERATION IN MICE
小鼠视网膜变性的微阵列分析
  • 批准号:
    7109159
  • 财政年份:
    2003
  • 资助金额:
    $ 24.83万
  • 项目类别:
MICROARRAY ANALYSIS OF RETINAL DEGENERATION IN MICE
小鼠视网膜变性的微阵列分析
  • 批准号:
    6803002
  • 财政年份:
    2003
  • 资助金额:
    $ 24.83万
  • 项目类别:
MICROARRAY ANALYSIS OF RETINAL DEGENERATION IN MICE
小鼠视网膜变性的微阵列分析
  • 批准号:
    7267007
  • 财政年份:
    2003
  • 资助金额:
    $ 24.83万
  • 项目类别:
MICROARRAY ANALYSIS OF RETINAL DEGENERATION IN MICE
小鼠视网膜变性的微阵列分析
  • 批准号:
    6931535
  • 财政年份:
    2003
  • 资助金额:
    $ 24.83万
  • 项目类别:

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Identification of candidate genes responsible for an increased susceptibility of age-related macular degeneration using an animal model and its application to gene diagnosis.
使用动物模型鉴定导致年龄相关性黄斑变性易感性增加的候选基因及其在基因诊断中的应用。
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  • 财政年份:
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MT1-MMP-based Animal Model of Age-related Macular Degeneration (AMD)
基于 MT1-MMP 的年龄相关性黄斑变性 (AMD) 动物模型
  • 批准号:
    8101435
  • 财政年份:
    2008
  • 资助金额:
    $ 24.83万
  • 项目类别:
MT1-MMP-based Animal Model of Age-related Macular Degeneration (AMD)
基于 MT1-MMP 的年龄相关性黄斑变性 (AMD) 动物模型
  • 批准号:
    7481783
  • 财政年份:
    2008
  • 资助金额:
    $ 24.83万
  • 项目类别:
A novel molecular paradigm of age-related macular degeneration in view of the social trend in nocturnal: An approach using an animal model
鉴于夜间活动的社会趋势,年龄相关性黄斑变性的新分子范式:使用动物模型的方法
  • 批准号:
    20791248
  • 财政年份:
    2008
  • 资助金额:
    $ 24.83万
  • 项目类别:
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Generation and characterisation of an animal model for age-related macular degeneration
年龄相关性黄斑变性动物模型的生成和表征
  • 批准号:
    nhmrc : 211977
  • 财政年份:
    2002
  • 资助金额:
    $ 24.83万
  • 项目类别:
    NHMRC Project Grants
Age-Related Macular Degeneration: Genetic Variations and Animal Model
年龄相关性黄斑变性:遗传变异和动物模型
  • 批准号:
    7734626
  • 财政年份:
  • 资助金额:
    $ 24.83万
  • 项目类别:
Age-Related Macular Degeneration: Genetic Variations and Animal Model
年龄相关性黄斑变性:遗传变异和动物模型
  • 批准号:
    8737634
  • 财政年份:
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    $ 24.83万
  • 项目类别:
Age-Related Macular Degeneration: Genetic Variations and Animal Model
年龄相关性黄斑变性:遗传变异和动物模型
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    $ 24.83万
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Age-Related Macular Degeneration: Genetic Variations and Animal Model
年龄相关性黄斑变性:遗传变异和动物模型
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    $ 24.83万
  • 项目类别:
Age-Related Macular Degeneration: Genetic Variations and Animal Model
年龄相关性黄斑变性:遗传变异和动物模型
  • 批准号:
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