Project 1 - Molecular structure and function
Project 1 - Molecular structure and function
批准号:
10628928
负责人:
Francesca M Marassi
金额:
$63.79万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-07-01 至 2028-04-30
关键词:
AddressAffinityAge related macular degenerationAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease patientAmyloid beta-ProteinAtrophicBasal laminaBindingBinding ProteinsBiological AssayBlindnessBloodBlood capillariesBone remodelingBrainBruch&aposs basal membrane structureCaliforniaCell AdhesionCell NucleusCell modelCellsChemicalsChoroidComplementDataDepositionDevelopmentDiseaseDisease ProgressionDisease modelDrusenExtracellular MatrixEyeFluorescenceGlycoproteinsGoalsHemostatic functionHydroxyapatitesHydroxylationIn VitroInvestigationLengthLinkLipidsMedicalMineralsModelingMolecularMolecular StructureNMR SpectroscopyNatural ImmunityNeuronsNuclear Magnetic ResonancePathologicProcessPropertyProteinsResolutionRetinaRisk FactorsRoleSamplingSenile PlaquesSolidSpecificityStructureStructure of retinal pigment epitheliumSurfaceTestingTherapeutic AgentsTissuesUniversitiesVariantVitronectinbiophysical techniquescalcificationcalcification inhibitorcalcium phosphatecell motilitycomplex biological systemsexperimental studyextracellularmineralizationnovel diagnosticsnovel therapeuticsreconstitutionsensorsmall moleculesolid state nuclear magnetic resonancetau Proteinstrait
中文摘要
项目1总结
分子结构和功能。该区矿化钙磷矿床的异位聚集
眼睛和大脑是老年性黄斑变性(AMD)和阿尔茨海默病(AD)的标志。在……里面
除了无机成分,如羟基磷灰石(HAP),这些沉积物还含有脂质和
来自血液和细胞内的蛋白质。人们对钙化的过程知之甚少,直到现在。
不清楚为什么有些存款会进展到疾病状态,而另一些则不会。目前也不清楚是否
相关蛋白质参与矿化过程,或者如果它们沉积和积累在已经
预制羟基磷灰石表面。在这里,我们通过全面和
分子组成的化学、物理和结构性质的系统研究
与钙化沉积物相关,特别关注三种有效的成分:玻璃连蛋白
(VN)、淀粉样蛋白b(Ab)和Tau。VN是一种具有多种止血、细胞黏附功能的血糖蛋白。
以及迁移、先天免疫、组织和骨骼重塑。最近的研究表明,VN结合了这两种基因
具有化学特异性的可溶性钙和固体羟基磷灰石以及T400M VN变异是AMD的主要危险因素。
AB和Tau是AD中淀粉样斑块的已知成分,但它们也可在钙化中发现
在眼睛和大脑中沉积。首先,我们将研究这些蛋白质在钙化过程中的作用。
通过基于荧光的实验和结合研究。然后,我们将重建原始聚集体
羟基磷灰石、脂类和蛋白质在体外模拟病理性沉积形成。这些聚合将提供
用于分析蛋白质和脂质在钙化中的功能作用的平台,并将有助于发现小的
钙化的分子和生物分子抑制剂。最后,我们将使用固态核磁
核磁共振波谱测定钙化矿床中VN、Tau和Ab的结构
描述驱动它们组装的蛋白质-矿物质相互作用。这一信息将对
了解钙化的分子机制,并最终开发新的诊断方法
和治疗剂。
英文摘要
PROJECT 1 SUMMARY
Molecular structure and function. The ectopic accumulation of mineralized calcium-phosphate deposits in
the eye and brain is a hallmark of Age-Related Macular Degeneration (AMD) and Alzheimer’s Disease (AD). In
addition to inorganic components, such as hydroxyapatite (HAP), these deposits also contain lipids and
proteins of both blood and intracellular origin. The process of calcification is poorly understood, and it remains
unclear why some deposits progress to the disease state while others do not. It is also not clear if the
associated proteins are involved in the mineralization process, or if they deposit and accumulate on the already
pre-formed hydroxyapatite surface. Here, we address these important questions by comprehensive and
systematic investigation of the chemical, physical and structural properties of the molecular components
associated with calcified deposits, with particular focus on three validated constituents: the proteins vitronectin
(Vn), amyloid-b (Ab) and Tau. Vn is a blood glycoprotein with diverse functions in hemostasis, cell adhesion
and migration, innate immunity, tissue and bone remodeling. Recent studies have indicated that Vn binds both
soluble Ca2+ and solid HAP with chemical specificity and the T400M Vn variant is a major risk factor for AMD.
Ab and Tau are well known components of amyloid plaques in AD, but they are also found in calcification
deposits in the eye and the brain. First, we will investigate the role of these proteins in the calcification process
through fluorescence-based experiments and binding studies. Then, we will reconstitute proto-aggregates of
HAP, lipids and proteins to model pathological deposit formation in vitro. These aggregates will provide a
platform for assaying the functional roles of proteins and lipids in calcification and will aid the discovery of small
molecule and biomolecular inhibitors of calcification. And finally, we will use solid-state nuclear magnetic
resonance (NMR) spectroscopy to determine the structures of Vn, Tau and Ab within calcified deposits and to
describe the protein-mineral interactions that drive their assembly. This information will be essential for
understanding the molecular mechanism of calcification and, ultimately, for the development of new diagnostic
and therapeutic agents.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Molecular mechanisms of calcification: roles and opportunities in diseases of aging
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批准号:10628925
-
项目类别:
-
资助金额:$262.85万
-
财政年份:2023
-
负责人:Francesca M Marassi
-
依托单位:
Core A - Administration
-
批准号:10628926
-
项目类别:
-
资助金额:$14.55万
-
财政年份:2023
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负责人:Francesca M Marassi
-
依托单位:
Core B - Biomolecular tools
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批准号:10628927
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项目类别:
-
资助金额:$37.0万
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财政年份:2023
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负责人:Francesca M Marassi
-
依托单位:
Membrane Protein Effectors of Pathogen Interactions With Host
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批准号:10630318
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项目类别:
-
资助金额:$64.74万
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财政年份:2016
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负责人:Francesca M Marassi
-
依托单位:
Membrane Protein Effectors of Pathogen Interactions With Host
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批准号:10207010
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项目类别:
-
资助金额:$80.93万
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财政年份:2016
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负责人:Francesca M Marassi
-
依托单位:
Membrane protein effectors of pathogen interactions with host
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批准号:9071833
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项目类别:
-
资助金额:$75.21万
-
财政年份:2016
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负责人:Francesca M Marassi
-
依托单位:
Membrane Protein Effectors of Pathogen Interactions With Host
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批准号:10689583
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项目类别:
-
资助金额:$44.23万
-
财政年份:2016
-
负责人:Francesca M Marassi
-
依托单位:
Membrane protein effectors of pathogen interactions with host
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批准号:9276714
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项目类别:
-
资助金额:$75.21万
-
财政年份:2016
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负责人:Francesca M Marassi
-
依托单位:
Membrane Protein Effectors of Pathogen Interactions With Host
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批准号:10404547
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项目类别:
-
资助金额:$25.45万
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财政年份:2016
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负责人:Francesca M Marassi
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依托单位:
600 MHz NMR/MRI Console
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批准号:9194544
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项目类别:
-
资助金额:$35.25万
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财政年份:2015
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负责人:Francesca M Marassi
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依托单位:
Membrane protein structure in lipido: computational developments.
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批准号:8686588
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项目类别:
-
资助金额:$33.12万
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财政年份:2014
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负责人:Francesca M Marassi
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依托单位:
Membrane protein structure in lipido: computational developments.
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批准号:8928230
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项目类别:
-
资助金额:$37.05万
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财政年份:2014
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负责人:Francesca M Marassi
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依托单位:
Host recognition by pathogenic yersiniae
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批准号:8667480
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项目类别:
-
资助金额:$40.11万
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财政年份:2012
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负责人:Francesca M Marassi
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依托单位:
Host recognition by pathogenic yersiniae
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批准号:8852632
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项目类别:
-
资助金额:$39.97万
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财政年份:2012
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负责人:Francesca M Marassi
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依托单位:
Host recognition by pathogenic yersiniae
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批准号:8386532
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项目类别:
-
资助金额:$48.8万
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财政年份:2012
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负责人:Francesca M Marassi
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依托单位:
Host recognition by pathogenic yersiniae
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批准号:8548374
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项目类别:
-
资助金额:$38.84万
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财政年份:2012
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负责人:Francesca M Marassi
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依托单位:
Computational methods for NMR structure determination of proteins in membranes
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批准号:8136905
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项目类别:
-
资助金额:$21.83万
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财政年份:2010
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负责人:Francesca M Marassi
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依托单位:
Computational methods for NMR structure determination of proteins in membranes
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批准号:7979041
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项目类别:
-
资助金额:$29.11万
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财政年份:2010
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负责人:Francesca M Marassi
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依托单位:
Assays and Screens
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批准号:7575458
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项目类别:
-
资助金额:$39.09万
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财政年份:2009
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负责人:Francesca M Marassi
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依托单位:
Structures of membrane-bound Bcl-2 apoptotic proteins
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批准号:7861636
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项目类别:
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资助金额:$10.43万
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财政年份:2009
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负责人:Francesca M Marassi
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依托单位:
海外基金