Targeting the PMP22 Protein to Develop Leads Against Charcot-Marie-Tooth Disease

靶向 PMP22 蛋白开发抗腓骨肌萎缩症的先导药物

基本信息

  • 批准号:
    10331038
  • 负责人:
  • 金额:
    $ 19.81万
  • 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:
    2021-01-20 至 2022-12-31
  • 项目状态:
    已结题

项目摘要

Project Summary Charcot-Marie-Tooth Disease (CMTD) is a debilitating hereditary peripheral neuropathy that afflicts 1:2500 humans. The hallmark of CTMD pathology is severely defective PNS myelin. There is currently no pharmacological treatment or cure for this disease. Over 75% of all cases of CMTD are caused by Schwann cell overexpression of wild type (WT) peripheral myelin protein (PMP22) due to trisomy, underexpression of PMP22 (for the WT/null case), or genetically dominant heterozygous (WT/mutant) mutations that alter the PMP22 protein sequence. WT PMP22 is known to properly fold and traffic with only 20% efficiency under healthy conditions. Our driving rationale is that small molecules that tune either the expression levels or in vivo folding efficiency of PMP22 have the potential to be effective therapeutic agents. Drugs that reduce expression of the protein are likely to prove effective against the most common form of CMTD (Type 1A) caused by trisomy-based overexpression. On the other hand, drugs that act as folding correctors or expression enhancers are likely to prove effective for forms of CMTD caused by underexpression and/or misfolding of PMP22. The Specific Aims of this project are designed to establish the foundations for a drug discovery program to develop therapeutic compounds for the most common forms of Charcot-Marie-Tooth Disease (CMTD), which are caused by genetic variations that impact the PMP22 gene that encodes peripheral myelin protein 22 (PMP22), a tetraspan membrane protein. These Aims are: Aim 1. Develop a primary assay that can be implemented in high throughput screening (HTS) mode to identify small molecules that alter the total expression of wild type (WT) and disease mutant forms of PMP22, or that enhance the cell surface membrane trafficking of the protein. Aim 2. Conduct primary screens to discover and characterize lead compounds that modulate total expression levels of PMP22 and/or that enhance PMP22 cell surface trafficking efficiency. Determine hit concentration-response (potency) curves. Aim 3. Conduct a secondary screen of hits using Schwann cells and test for hit efficacy in a myelination assay. Conduct biophysical studies to test whether lead compounds act in a way what involves direct binding to the PMP22 protein and also test for their impact on PMP22 protein stability. Successful completion of this project will provide a series of lead compounds that will be ready for future medicinal chemistry optimization of lead compound structures, efficacy testing in available mouse and rat models of CMTD, and pre-clinical testing.
项目摘要 腓骨肌萎缩症(CMTD)是一种使人衰弱的遗传性周围神经病变,其发病率为1:2500 人类CTMD病理学的标志是严重缺陷的PNS髓鞘。目前没有 对这种疾病的药物治疗或治愈。超过75%的CMTD病例是由以下原因引起的 由于三体性导致的野生型(WT)外周髓鞘蛋白(PMP 22)的雪旺细胞过表达, PMP 22低表达(WT/null情况)或遗传显性杂合子(WT/突变体) 改变PMP 22蛋白序列的突变。已知WT PMP 22可以正确折叠并与 只有20%的效率。我们的基本原理是, PMP 22的表达水平或体内折叠效率具有有效治疗的潜力 剂.减少蛋白质表达的药物可能被证明对最常见的 由基于三体的过表达引起的CMTD形式(1A型)。另一方面,药物作为 折叠校正剂或表达增强剂可能证明对由以下引起的CMTD形式有效: PMP 22的低表达和/或错误折叠。该项目的具体目标是建立 药物发现计划的基础,为最常见的 Charcot-Marie-Tooth病(CMTD)是由遗传变异引起的, 编码外周髓磷脂蛋白22(PMP 22)(一种四面体膜蛋白)的PMP 22基因。 这些目标是: 目标1。开发可在高通量筛选(HTS)中实施的初步测定 鉴定改变野生型(WT)和疾病突变体的总表达的小分子的模式 PMP 22的形式,或增强蛋白质的细胞表面膜运输。 目标二。进行初步筛选,以发现和表征调节总 在一些实施方案中,本发明的组合物可提高PMP 22的表达水平和/或增强PMP 22细胞表面运输效率。确定命中 浓度-响应(效价)曲线。 目标3。使用施旺细胞进行命中的二次筛选,并在一个实验室中测试命中功效。 髓鞘形成测定。进行生物物理研究,以测试铅化合物是否以某种方式起作用, 涉及直接结合到PMP 22蛋白,并且还测试它们对PMP 22蛋白稳定性的影响。 该项目的成功完成将提供一系列先导化合物, 为了将来药物化学优化先导化合物结构, 可用的CMTD小鼠和大鼠模型以及临床前试验。

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 }}

CHARLES R SANDERS其他文献

CHARLES R SANDERS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('CHARLES R SANDERS', 18)}}的其他基金

Cholesterol and the Amyloid Precursor Protein
胆固醇和淀粉样前体蛋白
  • 批准号:
    8529109
  • 财政年份:
    2013
  • 资助金额:
    $ 19.81万
  • 项目类别:
Cholesterol and the Amyloid Precursor Protein
胆固醇和淀粉样前体蛋白
  • 批准号:
    8839797
  • 财政年份:
    2013
  • 资助金额:
    $ 19.81万
  • 项目类别:
Cholesterol and the Amyloid Precursor Protein
胆固醇和淀粉样前体蛋白
  • 批准号:
    8642200
  • 财政年份:
    2013
  • 资助金额:
    $ 19.81万
  • 项目类别:
Structure Function Analysis of Integrins alpha1beta1 and alpha2beta2
整合素α1β1和α2β2的结构功能分析
  • 批准号:
    9270816
  • 财政年份:
    2010
  • 资助金额:
    $ 19.81万
  • 项目类别:
Structure Function Analysis of Integrins alpha1beta1 and alpha2beta2
整合素α1β1和α2β2的结构功能分析
  • 批准号:
    8500247
  • 财政年份:
    2010
  • 资助金额:
    $ 19.81万
  • 项目类别:
FASEB Summer Research Conference on Molecular Biophysics of Cellular Membranes
FASEB 细胞膜分子生物物理学夏季研究会议
  • 批准号:
    8004602
  • 财政年份:
    2010
  • 资助金额:
    $ 19.81万
  • 项目类别:
Structure Function Analysis of Integrins alpha1beta1 and alpha2beta2
整合素α1β1和α2β2的结构功能分析
  • 批准号:
    8286378
  • 财政年份:
    2010
  • 资助金额:
    $ 19.81万
  • 项目类别:
Structure Function Analysis of Integrins alpha1beta1 and alpha2beta2
整合素α1β1和α2β2的结构功能分析
  • 批准号:
    8002171
  • 财政年份:
    2010
  • 资助金额:
    $ 19.81万
  • 项目类别:
Project 3
项目3
  • 批准号:
    8151962
  • 财政年份:
    2010
  • 资助金额:
    $ 19.81万
  • 项目类别:
Structure Function Analysis of Integrins alpha1beta1 and alpha2beta2
整合素α1β1和α2β2的结构功能分析
  • 批准号:
    8097972
  • 财政年份:
    2010
  • 资助金额:
    $ 19.81万
  • 项目类别:

相似海外基金

Linkage of HIV amino acid variants to protective host alleles at CHD1L and HLA class I loci in an African population
非洲人群中 HIV 氨基酸变异与 CHD1L 和 HLA I 类基因座的保护性宿主等位基因的关联
  • 批准号:
    502556
  • 财政年份:
    2024
  • 资助金额:
    $ 19.81万
  • 项目类别:
Olfactory Epithelium Responses to Human APOE Alleles
嗅觉上皮对人类 APOE 等位基因的反应
  • 批准号:
    10659303
  • 财政年份:
    2023
  • 资助金额:
    $ 19.81万
  • 项目类别:
Deeply analyzing MHC class I-restricted peptide presentation mechanistics across alleles, pathways, and disease coupled with TCR discovery/characterization
深入分析跨等位基因、通路和疾病的 MHC I 类限制性肽呈递机制以及 TCR 发现/表征
  • 批准号:
    10674405
  • 财政年份:
    2023
  • 资助金额:
    $ 19.81万
  • 项目类别:
An off-the-shelf tumor cell vaccine with HLA-matching alleles for the personalized treatment of advanced solid tumors
具有 HLA 匹配等位基因的现成肿瘤细胞疫苗,用于晚期实体瘤的个性化治疗
  • 批准号:
    10758772
  • 财政年份:
    2023
  • 资助金额:
    $ 19.81万
  • 项目类别:
Identifying genetic variants that modify the effect size of ApoE alleles on late-onset Alzheimer's disease risk
识别改变 ApoE 等位基因对迟发性阿尔茨海默病风险影响大小的遗传变异
  • 批准号:
    10676499
  • 财政年份:
    2023
  • 资助金额:
    $ 19.81万
  • 项目类别:
New statistical approaches to mapping the functional impact of HLA alleles in multimodal complex disease datasets
绘制多模式复杂疾病数据集中 HLA 等位基因功能影响的新统计方法
  • 批准号:
    2748611
  • 财政年份:
    2022
  • 资助金额:
    $ 19.81万
  • 项目类别:
    Studentship
Recessive lethal alleles linked to seed abortion and their effect on fruit development in blueberries
与种子败育相关的隐性致死等位基因及其对蓝莓果实发育的影响
  • 批准号:
    22K05630
  • 财政年份:
    2022
  • 资助金额:
    $ 19.81万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Genome and epigenome editing of induced pluripotent stem cells for investigating osteoarthritis risk alleles
诱导多能干细胞的基因组和表观基因组编辑用于研究骨关节炎风险等位基因
  • 批准号:
    10532032
  • 财政年份:
    2022
  • 资助金额:
    $ 19.81万
  • 项目类别:
Investigating the Effect of APOE Alleles on Neuro-Immunity of Human Brain Borders in Normal Aging and Alzheimer's Disease Using Single-Cell Multi-Omics and In Vitro Organoids
使用单细胞多组学和体外类器官研究 APOE 等位基因对正常衰老和阿尔茨海默病中人脑边界神经免疫的影响
  • 批准号:
    10525070
  • 财政年份:
    2022
  • 资助金额:
    $ 19.81万
  • 项目类别:
Leveraging the Evolutionary History to Improve Identification of Trait-Associated Alleles and Risk Stratification Models in Native Hawaiians
利用进化历史来改进夏威夷原住民性状相关等位基因的识别和风险分层模型
  • 批准号:
    10689017
  • 财政年份:
    2022
  • 资助金额:
    $ 19.81万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了