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

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.
项目总结/文摘

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(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:
    $ 44.38万
  • 项目类别:
The Role of Mia2 in Lipoprotein Biogenesis
Mia2 在脂蛋白生物发生中的作用
  • 批准号:
    8445830
  • 财政年份:
    2013
  • 资助金额:
    $ 44.38万
  • 项目类别:
The Role of Mia2 in Lipoprotein Biogenesis
Mia2 在脂蛋白生物发生中的作用
  • 批准号:
    8666803
  • 财政年份:
    2013
  • 资助金额:
    $ 44.38万
  • 项目类别:
Epigenomic Modulation of Cystic Fibrosis
囊性纤维化的表观基因组调节
  • 批准号:
    8435550
  • 财政年份:
    2010
  • 资助金额:
    $ 44.38万
  • 项目类别:
Epigenomic Modulation of Cystic Fibrosis
囊性纤维化的表观基因组调节
  • 批准号:
    7888788
  • 财政年份:
    2010
  • 资助金额:
    $ 44.38万
  • 项目类别:
Epigenomic Modulation of Cystic Fibrosis
囊性纤维化的表观基因组调节
  • 批准号:
    8212528
  • 财政年份:
    2010
  • 资助金额:
    $ 44.38万
  • 项目类别:
Epigenomic Modulation of Cystic Fibrosis
囊性纤维化的表观基因组调节
  • 批准号:
    8761533
  • 财政年份:
    2010
  • 资助金额:
    $ 44.38万
  • 项目类别:
Modulation of Lung Disease by Genetic/Epigenetic Profiling
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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