Using Genetic Diversity to Manage Neurological Disease
利用遗传多样性来治疗神经系统疾病
基本信息
- 批准号:10321554
- 负责人:
- 金额:$ 44.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAgingAllelesAlzheimer&aposs DiseaseAmino Acid SequenceAutomobile DrivingAutophagocytosisBasic ScienceBiochemicalBiological SciencesBirthBrainBuffersCellsCessation of lifeCharacteristicsChemicalsCholesterolCholesterol HomeostasisClinicalDiseaseDisease ManagementDisease ProgressionEnvironmentEtiologyGRP geneGaussian modelGenesGeneticGenetic DiseasesGenetic VariationGenomeGenotypeGoalsHeat-Shock Proteins 70Heat-Shock ResponseHumanIndividualInheritedKnowledgeLate Onset Alzheimer DiseaseLeadLearningLightLipidsLysosomesMachine LearningModernizationMolecularMolecular ChaperonesMolecular Mechanisms of ActionNeurodegenerative DisordersNiemann-Pick DiseasesPathologyPathway interactionsPatientsPhenotypePopulationProcessProteinsRare DiseasesResolutionRoleSignal PathwaySpecificityStressStructureSystemTarget PopulationsTherapeuticTherapeutic InterventionTimeUbiquitinUncertaintyUnited States National Library of MedicineVariantbasebiochemical toolsbiophysical toolscell typecholesterol controldruggable targetearly onsetfitnessgenomic variationhuman modelimprovedinsightloss of functionmulticatalytic endopeptidase complexnervous system disordernovelpolypeptideprecision medicinepreventprognosticprotein foldingprotein functionprotein misfoldingproteostasisrare genetic disorderrare variantresponsesmall moleculetooltrafficking
项目摘要
Project Summary/Abstract
Understanding and treating genome abnormalities that lead to rare genetic neurodegenerative diseases such as
Niemann-Pick C1 globally managing cholesterol homeostasis, or APOE alleles impacting cholesterol
homeostasis in the brain triggering late-onset Alzheimer’s disease (LOAD), present a major challenge from both
basic science and clinical perspectives. We have developed a Gaussian process regression (GPR) based
machine learning (ML) approach that captures for the first time genomic variation in the population to understand
the spatial covariance (SCV) relationships contributing to sequence-to-function-to-structure relationships in the
individual. Genetic disease is fundamentally a problem of understanding the impact of altered folding
intermediates found in response to variation in the protein fold and how they are managed by proteostasis.
Proteostasis encompasses a broad range of chaperone and degradative components that manage the synthesis,
folding/stability and function of the protein fold in response to inherited and environmental stress and aging. The
general premise of this proposal is to develop a deep genome-based understanding of proteostasis that will
teach us how to manage genetic diseases triggered by folding stress. The rationale for this proposal is that
sparse genetic diversity found in the population, when used as a collective through application of GRP-ML
defined SCV relationships, can provide us on a residue-by-residue basis insight into the folding intermediates
that contribute to disease for the entire polypeptide sequence. The objective of this proposal is to understand
the role of proteostasis in managing this genetic diversity for the benefit of therapeutic intervention. We
hypothesize that management of the polypeptide fold of disease-causing variant proteins found in the population
by targeting the function of the multivalent Hsp40 and Hsp70 co-chaperone/chaperone branch (the Hsp70 axis)
of the proteostasis network will enable precision correction of misfolding phenotypes found in neurodegenerative
disease. Our approach will study the impact of variation in the Niemann Pick C1 (NPC1) gene. NPC1 is an
inherited, autosomal recessive, disorder characterized by the abnormal accumulation of unesterified cholesterol
and other lipids in late endosomal (LE) and lysosome (Ly) compartments of all cell types. The primary effect of
NPC1 variation results in early onset neurodegenerative disease in response to loss of cholesterol homeostasis.
In Aim 1 we will explore the ability of small molecules to allosterically regulate the activity of components of the
Hsp70 axis to retune the synthesis, folding/stability, trafficking and/or function of NPC1 variants. In Aim 2 we
will explore the molecular mechanism of action (MoA) of the Hsp70 axis components that are responsible for
enabling NPC1 variant correction. Completion of both aims will generate a comprehensive assessment of the
role of Hsp70 axis in NPC1 disease progression and will be used as a guide for advancement of a precision
medicine approach to reduce or prevent the onset of neurodegenerative disease triggered by genomic variation
in NPC1 population.
项目摘要/摘要
了解和治疗导致罕见遗传性神经退行性疾病的基因组异常,如
Niemann-Pick C1全球管理胆固醇稳态,或影响胆固醇的APOE等位基因
引发迟发性阿尔茨海默病(LOAD)的大脑内稳态是来自两个人的主要挑战
基础科学和临床前景。我们开发了一个基于高斯过程回归(GPR)的方法
机器学习(ML)方法首次捕获种群中的基因组变异以了解
空间协方差(SCV)关系在序列-功能-结构关系中起作用
个人的。基因疾病从根本上说是一个理解折叠改变的影响的问题
对蛋白质折叠的变化作出反应的中间体,以及它们是如何通过蛋白质平衡来管理的。
蛋白质组学包括管理合成的广泛的伴侣和降解成分,
蛋白质折叠的稳定性和功能对遗传和环境压力以及衰老的反应。这个
这一提议的总体前提是发展对蛋白质调控的深入的基于基因组的理解,这将
教我们如何管理由折叠压力引发的遗传病。这项提议的理由是
在种群中发现的稀疏遗传多样性,当通过应用GRP-ML作为一个集体使用时
定义的SCV关系,可以让我们在逐个残基的基础上深入了解折叠中间体
这会导致整个多肽序列的疾病。这项建议的目标是理解
蛋白质平衡在管理这种遗传多样性中的作用,以利于治疗干预。我们
假设在人群中发现的致病变异蛋白的多肽折叠的管理
通过靶向多价Hsp40和Hsp70共伴侣/伴侣分支(Hsp70轴)的功能
蛋白质平衡网络的研究将使在神经退行性变中发现的错误折叠表型得到精确纠正
疾病。我们的方法将研究Niemann Pick C1(NPC1)基因变异的影响。NPC1是一个
遗传性,常染色体隐性遗传,以未酯化胆固醇异常积聚为特征的疾病
和其他脂类存在于所有细胞类型的晚期内小体(LE)和溶酶体(Ly)间。的主要效果
NPC1基因变异会导致早期神经退行性疾病,以应对胆固醇稳态的丧失。
在目标1中,我们将探索小分子以变构方式调节
HSP70轴调节NPC1变异体的合成、折叠/稳定性、运输和/或功能。在《目标2》中,我们
将探索负责Hsp70轴组件的分子作用机制(MOA)
启用NPC1变体更正。完成这两个目标将产生对
Hsp70轴在NPC1疾病进展中的作用并将被用作提高精确度的指南
减少或预防由基因组变异引发的神经退行性疾病的医学方法
在NPC1人群中。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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William Edward Balch其他文献
William Edward Balch的其他文献
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{{ truncateString('William Edward Balch', 18)}}的其他基金
Applying Spatial Covariance to Understand Human Variation in Genetic Disease
应用空间协方差来了解遗传疾病的人类变异
- 批准号:
10734426 - 财政年份:2023
- 资助金额:
$ 44.38万 - 项目类别:
Using Genetic Diversity to Manage Neurological Disease
利用遗传多样性来治疗神经系统疾病
- 批准号:
10538562 - 财政年份:2021
- 资助金额:
$ 44.38万 - 项目类别:
Using Genetic Diversity to Manage Neurological Disease
利用遗传多样性来治疗神经系统疾病
- 批准号:
10706236 - 财政年份:2021
- 资助金额:
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通过遗传/表观遗传分析调节肺部疾病
- 批准号:
10369651 - 财政年份:2010
- 资助金额:
$ 44.38万 - 项目类别:
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