The Importance of Prolyl 3-hydroxylation in recessive Osteogenesis Imperfecta
脯氨酰 3-羟基化在隐性成骨不全中的重要性
基本信息
- 批准号:8036053
- 负责人:
- 金额:$ 3.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-03-01 至 2014-02-28
- 项目状态:已结题
- 来源:
- 关键词:2-oxoglutarate 3-dioxygenase prolineAddressAffectAmino AcidsCartilageCell Culture TechniquesCellsCollagenCollagen Type IComplexCraniofacial AbnormalitiesCyclosporineDataDefectFibrillar CollagenGoalsHumanHydroxylationHydroxyprolineIn VitroIsomeraseKnock-in MouseLightLysineMethodologyMixed Function OxygenasesModificationMolecularMolecular AbnormalityMolecular ConformationMutationOsteogenesis ImperfectaPathogenesisPatientsPeptidylprolyl IsomerasePhenotypePhysiologyPoint MutationPositioning AttributePost-Translational Protein ProcessingProcessProcollagenProlineProteinsRegulationRelative (related person)RoleStructurecis-trans-Isomerasescyclophilin Bin vivoinhibitor/antagonistloss of functionmembermolecular markermouse modelmutantprotein functionprotein protein interactionprotein structurepublic health relevanceresearch studytriple helixtype I collagen alpha 1
项目摘要
DESCRIPTION (provided by applicant): The goal of this project is to study the molecular pathogenesis of recessive osteogenesis imperfecta (OI)- a brittle bone disease with craniofacial abnormalities. Morello et. al. first identified mutations in Cartilage Associated Protein (CRTAP) as causative of OI Type VII, a recessive OI[3]. Additionally, mutations to prolyl 3- hydroxylase (P3H1) have been identified as causative of recessive OI[4]. CRTAP and P3H1 form a complex with cyclophilin B (CypB) and this complex functions to 3-hydroxylate a single proline residue on the alpha 1 chain of type I collagen[2]. In addition to its function as a 3-hydroxylase, CypB functions as a cis/trans isomerase (PPIase)[9]. Many of the amino acid residues present in the triple helix region are in the cis form and collagen will not fold properly unless all bonds are in the trans conformation[11]. Thus, the function of PPIase is essential for proper collagen folding. Interestingly, the inhibition of CypB by cyclosporin A results in overmodified collagen and a delay in collagen secretion- similar to the collagen defects observed in recessive OI patints[19]. Recently, data suggest that the presence of 3-hydroxyproline may stabilize the helix domain[7]. However, its presence or absence is not likely to affect the structural integrity of collagen, but its absence may disrupt protein-protein interactions integral for proper collagen folding[7]. Preliminary data demonstrate that P3H1 and CRTAP stabilize each other. Thus, when one complex member is mutant, the other is degraded. Since all identified CRTAP and P3H1 mutations are hypomorphic or null, it is unclear whether the 3- hydroxylation function and/or the PPIase function are important in the molecular pathogenesis of recessive OI. Thus, this project aims to study the contribution on P3H1 hydroxylase activity and how it pertains to the pathogenesis of recessive OI by inactivating the hydroxylase domain while maintaining the protein structure. To address the contribution of P3H1 hydroxylase activity, the following experiments are proposed: 1)study the consequences of 3-hydroxylase inactivation on collagen secretion, and modification by cell culture, and 2) assess whether 3-hydroxylation contributes to an osteoporotic phenotype by studying knock-in mice containing the point mutation demonstrated to best inactivate the hydroxylase function while maintaining the stability of the P3H1 complex.
Public Health Relevance: This project dissects the role of the enzymatic activity of the P3H1 protein within a collagen modifying complex that serves two roles in the processing of collagen. The results of this project will impact our understanding of the regulation of collagen processing and will shed light on the molecular abnormalities leading to recessive OI.
描述(由申请人提供):本项目的目标是研究隐性成骨骨不全(OI)的分子发病机制-一种颅面异常的脆骨疾病。Morello et.等人首先鉴定出Carcinoma相关蛋白(CRTAP)中的突变是VII型OI(一种隐性OI)的病因[3]。此外,脯氨酰3-羟化酶(P3 H1)突变已被确定为隐性OI的病因[4]。CRTAP和P3 H1与亲环蛋白B(CypB)形成复合物,该复合物的功能是3-羟基化I型胶原α 1链上的单个脯氨酸残基[2]。除了作为3-羟化酶的功能外,CypB还作为顺式/反式异构酶(PPI酶)[9]。三螺旋区中存在的许多氨基酸残基为顺式形式,除非所有键均为反式构象,否则胶原蛋白将无法正确折叠[11]。因此,PPIase的功能对于正确的胶原蛋白折叠至关重要。有趣的是,环孢菌素A对CypB的抑制导致过度修饰的胶原蛋白和胶原蛋白分泌的延迟-类似于在隐性OI患者中观察到的胶原蛋白缺陷[19]。最近,数据表明,3-羟脯氨酸的存在可以稳定螺旋结构域[7]。然而,它的存在或不存在不太可能影响胶原蛋白的结构完整性,但它的缺乏可能会破坏适当胶原蛋白折叠所必需的蛋白质-蛋白质相互作用[7]。初步数据表明,P3 H1和CRTAP相互稳定。因此,当一个复杂的成员是突变的,另一个是降解。由于所有确定的CRTAP和P3 H1突变是亚型或无效的,目前还不清楚是否3-羟基化功能和/或PPIase功能是重要的隐性OI的分子发病机制。因此,本项目旨在研究P3 H1羟化酶活性的贡献,以及它如何通过在保持蛋白质结构的同时使羟化酶结构域失活而与隐性OI的发病机制相关。为了解决P3 H1羟化酶活性的贡献,提出了以下实验:1)研究3-羟化酶失活对胶原分泌的影响,以及通过细胞培养进行修饰,和2)通过研究敲除,在含有点突变的小鼠中,证明最好地抑制羟化酶功能,同时保持P3 H1复合物的稳定性。
公共卫生相关性:该项目剖析了P3 H1蛋白的酶活性在胶原蛋白修饰复合物中的作用,该复合物在胶原蛋白的加工中起两种作用。该项目的结果将影响我们对胶原蛋白加工调节的理解,并将揭示导致隐性OI的分子异常。
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 }}
ERICA Paige HOMAN其他文献
ERICA Paige HOMAN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('ERICA Paige HOMAN', 18)}}的其他基金
The Importance of Prolyl 3-hydroxylation in recessive Osteogenesis Imperfecta
脯氨酰 3-羟基化在隐性成骨不全中的重要性
- 批准号:
8410477 - 财政年份:2010
- 资助金额:
$ 3.23万 - 项目类别:
The Importance of Prolyl 3-hydroxylation in recessive Osteogenesis Imperfecta
脯氨酰 3-羟基化在隐性成骨不全中的重要性
- 批准号:
7908229 - 财政年份:2010
- 资助金额:
$ 3.23万 - 项目类别:
The Importance of Prolyl 3-hydroxylation in recessive Osteogenesis Imperfecta
脯氨酰 3-羟基化在隐性成骨不全中的重要性
- 批准号:
8212319 - 财政年份:2010
- 资助金额:
$ 3.23万 - 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:
$ 3.23万 - 项目类别:
Fellowship
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:
$ 3.23万 - 项目类别:
Research Grant
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:
$ 3.23万 - 项目类别:
Continuing 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:
$ 3.23万 - 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:
$ 3.23万 - 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:
$ 3.23万 - 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:
$ 3.23万 - 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:
$ 3.23万 - 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:
$ 3.23万 - 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:
$ 3.23万 - 项目类别:
Research Grant