A new mouse model to study GBA1 mutation-associated diseases with multiple organs involvement

研究GBA1突变相关多器官疾病的新小鼠模型

基本信息

  • 批准号:
    10508985
  • 负责人:
  • 金额:
    $ 25.85万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-01 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

Project Summary: We aim to develop a new mouse model for studying diseases caused by GBA1 mutations in multiple organ systems. GBA1 encodes a lysosomal glucocerebrosidase (GCase) responsible for degradation of its glycosphingolipid substrates. Mutations in GBA1 gene disrupt GCase function and cause Gaucher disease (GD) that presents heterogeneous disease phenotypes in visceral or central nervous system (CNS) organs. Typical manifestations of visceral form GD1 include hepatosplenomegaly, anemia, thrombocytopenia and osteopenia. Neuronopathic GD (nGD, GD2 and GD3) are rapidly progressive CNS diseases leading to mortality and accompanied with visceral symptoms. GD affects multiple organs that align with the research mission of NIDDK (liver), NHLBI (lung), NINDS (CNS) and NIAMS (bone). GBA1 gene mutations are also genetic risks in developing Parkinson disease (PD). The approved therapies, Substrate Reduction Therapy (SRT) and Enzyme Replacement Therapy, are only effective in GD with visceral symptoms and do not treat CNS diseases. The effective disease modifying therapy is not available to treat PD. GBA1 mutation-caused diseases are complex affecting multiple organs. Faithful modeling of GD and GBA1-associated PD in an animal model is crucial to study the associated disease processes and to establish a clinically-relevant model for testing therapeutic approaches. A barrier in studying GBA1 mutation-associated diseases is the absence of animal models that recapitulate all aspect of human disease in multiple organs. Previously developed Gba1 mutant mouse models either show no detectable phenotype or affect restricted organs. Their nGD and PD phenotypes are very mild to absent. Our recent study has identified progranulin as a modifier of GCase. Deletion of progranulin in Gba1 mutant mice resulted in rapid progression of substrates accumulation, Gaucher-like macrophages and inflammation in liver, lung and brain organs, the typical GD phenotypes. This new model (termed PG9V) also developed neuronal phenotypes recapitulating nGD and PD. Our new PG9V model overcomes the limitations in the existing models. We hypothesize that genetic modification of Gba1 mutant mice by progranulin deletion impacts inflammation and glycosphingolipid metabolism in visceral and CNS organs, establishing a novel clinically-relevant animal model for GD and PD. We will characterize visceral GD phenotypes (Aim 1) and evaluate CNS phenotypes (Aim 2) in PG9V mouse model to establish criteria for testing therapies. Furthermore, we will test if SRT compound alleviate the disease in PG9V mice to determine preclinical value of PG9V model. This new GBA1 mutation-associated mouse model represents a major advance forward from existing mouse models. Comprehensive characterization of PG9V mice will facilitate pathophysiological studies and enables therapy evaluation and toxicity testing in a single model with multiple organs involvement.
项目概要: 我们的目标是开发一种新的小鼠模型,用于研究多器官中GBA 1突变引起的疾病。 系统. GBA 1编码一种溶酶体葡糖脑苷脂酶(GCase),负责降解其 鞘糖脂底物。GBA 1基因突变破坏GCase功能并导致戈谢病(GD) 其在内脏或中枢神经系统(CNS)器官中呈现异质性疾病表型。典型 内脏型GD 1的表现包括肝脾肿大、贫血、血小板减少和骨质减少。 神经元病性GD(nGD、GD2和GD3)是导致死亡的快速进展性CNS疾病, 伴有内脏症状。GD影响与NIDDK研究使命一致的多个器官 (肝)、NHLBI(肺)、NINDS(CNS)和NIAMS(骨)。GBA1基因突变也是遗传风险, 帕金森病(Parkinson Disease,PD)已批准的疗法,底物减少疗法(SRT)和酶 替代疗法仅对伴有内脏症状的GD有效,不治疗CNS疾病。的 有效的疾病改善疗法不能用于治疗PD。GBA1突变引起的疾病是复杂的 影响多个器官在动物模型中对GD和GBA 1相关PD进行准确建模, 研究相关的疾病过程,并建立一个临床相关的模型,用于测试治疗 接近。研究GBA 1突变相关疾病的一个障碍是缺乏动物模型, 在多个器官中概括人类疾病的所有方面。先前开发的Gba1突变小鼠模型 要么没有表现出可检测的表型,要么影响有限的器官。他们的nGD和PD表型非常轻微, 无托叶我们最近的研究已经确定颗粒蛋白前体作为GCase的修饰剂。Gba1中颗粒蛋白前体的缺失 突变小鼠导致底物积累、戈谢样巨噬细胞和 肝、肺和脑器官的炎症,典型的GD表型。这款新型号(称为PG9V)还 发展了概括nGD和PD的神经元表型。我们的新型PG9V型号克服了 现有的模型。我们假设通过颗粒蛋白前体缺失对Gba1突变小鼠进行遗传修饰, 影响内脏和CNS器官的炎症和鞘糖脂代谢,建立了一种新的 GD和PD的临床相关动物模型。我们将描述内脏GD表型(目的1), 在PG9V小鼠模型中评价CNS表型(目的2)以建立用于测试疗法的标准。此外,委员会认为, 我们将测试SRT化合物是否减轻PG9V小鼠的疾病以确定PG9V模型的临床前价值。 这种新的GBA 1突变相关小鼠模型代表了现有小鼠模型的重大进步。 模型PG9V小鼠的全面表征将促进病理生理学研究, 在涉及多个器官的单一模型中进行治疗评价和毒性测试。

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 }}

Chuanju Liu其他文献

Chuanju Liu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('Chuanju Liu', 18)}}的其他基金

Targeting TNF Receptors to Inhibit Inflammation and to Prompt Bone Regeneration in Type 1 Diabetes
靶向 TNF 受体抑制炎症并促进 1 型糖尿病的骨再生
  • 批准号:
    10915157
  • 财政年份:
    2023
  • 资助金额:
    $ 25.85万
  • 项目类别:
The immunological mechanism of PGRNs anti-inflammatory effect
PGRNs抗炎作用的免疫学机制
  • 批准号:
    10912299
  • 财政年份:
    2023
  • 资助金额:
    $ 25.85万
  • 项目类别:
The Role of Sodium Channel Nav1.7 in Osteoarthritis - Resubmission - 1
钠通道 Nav1.7 在骨关节炎中的作用 - 重新提交 - 1
  • 批准号:
    10390155
  • 财政年份:
    2022
  • 资助金额:
    $ 25.85万
  • 项目类别:
A new mouse model to study GBA1 mutation-associated diseases with multiple organs involvement
研究GBA1突变相关多器官疾病的新小鼠模型
  • 批准号:
    10651885
  • 财政年份:
    2022
  • 资助金额:
    $ 25.85万
  • 项目类别:
Targeting TNF Receptors to Inhibit Inflammation and to Prompt Bone Regeneration in Type 1 Diabetes - Resubmission - 1
靶向 TNF 受体抑制 1 型糖尿病炎症并促进骨再生 - 重新提交 - 1
  • 批准号:
    10453563
  • 财政年份:
    2020
  • 资助金额:
    $ 25.85万
  • 项目类别:
Targeting TNF Receptors to Inhibit Inflammation and to Prompt Bone Regeneration in Type 1 Diabetes - Resubmission - 1
靶向 TNF 受体抑制 1 型糖尿病炎症并促进骨再生 - 重新提交 - 1
  • 批准号:
    10218061
  • 财政年份:
    2020
  • 资助金额:
    $ 25.85万
  • 项目类别:
Progranulin: A Novel Gene in Gaucher Diseases
颗粒体蛋白前体:戈谢病的一个新基因
  • 批准号:
    10251862
  • 财政年份:
    2017
  • 资助金额:
    $ 25.85万
  • 项目类别:
Progranulin: A Novel Gene in Gaucher Diseases
颗粒体蛋白前体:戈谢病的一个新基因
  • 批准号:
    10011889
  • 财政年份:
    2017
  • 资助金额:
    $ 25.85万
  • 项目类别:
Progranulin Intervention in Inflammatory Bowel Diseases
颗粒体蛋白前体干预炎症性肠病
  • 批准号:
    8708276
  • 财政年份:
    2013
  • 资助金额:
    $ 25.85万
  • 项目类别:
The Role of PGRN Growth Factor in Osteoarthritis
PGRN 生长因子在骨关节炎中的作用
  • 批准号:
    8698896
  • 财政年份:
    2013
  • 资助金额:
    $ 25.85万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 25.85万
  • 项目类别:
    Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 25.85万
  • 项目类别:
    Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 25.85万
  • 项目类别:
    Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 25.85万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 25.85万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 25.85万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 25.85万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 25.85万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 25.85万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 25.85万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了