Pathogenesis and motor neuron degeneration of a novel disease associated with a P158A mutation in NAMPT

与 NAMPT P158A 突变相关的新型疾病的发病机制和运动神经元变性

基本信息

  • 批准号:
    10444087
  • 负责人:
  • 金额:
    $ 49.92万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-02-15 至 2027-01-01
  • 项目状态:
    未结题

项目摘要

Project Summary Nicotinamide adenine dinucleotide (NAD+) is a cofactor required for glycolysis, the tricarboxylic acid cycle (TCA) and enzymatic reaction in electron transport chain (ETC). In mammalian cells, NAD+ salvage pathway, where nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme, is the predominant pathway for NAD+ biosynthesis. Although the dysregulation of NAD+ in aging and neurodegerative diseases has been reported, genetic diseases caused by NAMPT variants have not been clinically recognized and understood. Here we identified the first case of an inherited neurological disease caused by a homozygous single nucleotide polymorphism (SNP), i.e., a P158A mutation in the coding region of NAMPT gene. The major clinical features of patients include impaired motor coordination, muscle weakness, atrophy of lower extremities, positive Babiński sign. The patients were diagnosed as hereditary motor and sensory neuropathy involving axonal degeneration and neuromuscular junction (NMJ) dysfunction. Using skin-derived patient fibroblasts (p-FBs), our preliminary studies found that P158A mutation causes reduced bioenergetics, mitochondrial dysfunction, and decreased enzymatic activity of NAMPT for NAD+ biosynthesis compared with healthy control fibroblasts (c-FBs). The results indicate the pathological conditions related to the patients is initially resulted from bioenergetic stress and ultimately from neuronal and muscular degeneration. Thus, our project goal is to understand the pathogenesis and the mechanism of neuronal and muscular degeneration of this new disease. To achieve our goal, we generated many molecular tools including P158A-NAMPT mutant mice, c- & p-FBs-derived induced pluripotent stem cells (c- & p-iPSCs including isogenic and patient like p-iPSCs), and iPSC-induced motor neurons (c- & p- iMNs). We propose three Specific Aims. Aim 1 will test the hypothesis P158A mutation in NAMPT causes mitochondrial and synaptic dysfunction of p-iMNs. Using iMNs, we will study the effect of P158A mutation on cellular bioenergetics, glycolytic metabolism and mitochondrial respiration. We will also conduct combined metabolomic and transcriptional profiling to determine the molecular base of metabolic changes caused by P158A mutation. Aim 2 will test the hypothesis that P158A mutation in NAMPT causes MN degeneration. Using the mutant mice, we will study disease progression, upper and lower MN degeneration. We will use electrophysiological and two-photon (2-P) imaging to study the effect of P158A mutation on sensory response and cytosolic and mitochondrial Ca2+ signaling. Aim 3 will test the hypothesis that P158A mutation in NAMPT causes NMJ abnormalities and muscle degeneration. We will assess structural and functional abnormalities of NMJs and muscle contractile response of semitendinosus muscles isolated from the symptomatic mutant mice. A human disease caused by NAMPT mutation has not been reported so far. Our application represents a first in-depth study on the pathogenesis and mechanism of motor neuron and muscle degeneration of a new neurological disease caused by a mutation in NAMPT gene.
项目总结

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 }}

Shinghua Ding其他文献

Shinghua Ding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('Shinghua Ding', 18)}}的其他基金

A novel therapeutic approach for Alzheimer Disease (AD)
阿尔茨海默病(AD)的新治疗方法
  • 批准号:
    10740016
  • 财政年份:
    2023
  • 资助金额:
    $ 49.92万
  • 项目类别:
Pathogenesis and motor neuron degeneration of a novel disease associated with a P158A mutation in NAMPT
与 NAMPT P158A 突变相关的新型疾病的发病机制和运动神经元变性
  • 批准号:
    10563210
  • 财政年份:
    2022
  • 资助金额:
    $ 49.92万
  • 项目类别:
THE ROLE AND MECHANISMS OF PBEF IN ACUTE BRAIN INJURY AND LONG-TERM STROKE OUTCOMES AFTER FOCAL ISCHEMIC STROKE
PBEF 在急性脑损伤和局灶性缺血性卒中后长期卒中结局中的作用和机制
  • 批准号:
    9535511
  • 财政年份:
    2015
  • 资助金额:
    $ 49.92万
  • 项目类别:
THE ROLE AND MECHANISMS OF PBEF IN ACUTE BRAIN INJURY AND LONG-TERM STROKE OUTCOMES AFTER FOCAL ISCHEMIC STROKE
PBEF 在急性脑损伤和局灶性缺血性卒中后长期卒中结局中的作用和机制
  • 批准号:
    9147010
  • 财政年份:
    2015
  • 资助金额:
    $ 49.92万
  • 项目类别:
The Role of Gliotransmission in Cerebral Ischemia
胶质细胞传输在脑缺血中的作用
  • 批准号:
    8641732
  • 财政年份:
    2010
  • 资助金额:
    $ 49.92万
  • 项目类别:
The Role of Gliotransmission in Cerebral Ischemia
胶质细胞传输在脑缺血中的作用
  • 批准号:
    8259199
  • 财政年份:
    2010
  • 资助金额:
    $ 49.92万
  • 项目类别:
Reactive astrocytes in neural regeneration and brain recovery after focal ischemic stroke
反应性星形胶质细胞在局灶性缺血性中风后神经再生和大脑恢复中的作用
  • 批准号:
    10458598
  • 财政年份:
    2010
  • 资助金额:
    $ 49.92万
  • 项目类别:
The Role of Gliotransmission in Cerebral Ischemia
胶质细胞传输在脑缺血中的作用
  • 批准号:
    8460525
  • 财政年份:
    2010
  • 资助金额:
    $ 49.92万
  • 项目类别:
Reactive astrocytes in neural regeneration and brain recovery after focal ischemic stroke
反应性星形胶质细胞在局灶性缺血性中风后神经再生和大脑恢复中的作用
  • 批准号:
    10220140
  • 财政年份:
    2010
  • 资助金额:
    $ 49.92万
  • 项目类别:
The Role of Gliotransmission in Cerebral Ischemia
胶质细胞传输在脑缺血中的作用
  • 批准号:
    8071506
  • 财政年份:
    2010
  • 资助金额:
    $ 49.92万
  • 项目类别:

相似海外基金

Interplay between Aging and Tubulin Posttranslational Modifications
衰老与微管蛋白翻译后修饰之间的相互作用
  • 批准号:
    24K18114
  • 财政年份:
    2024
  • 资助金额:
    $ 49.92万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
The Canadian Brain Health and Cognitive Impairment in Aging Knowledge Mobilization Hub: Sharing Stories of Research
加拿大大脑健康和老龄化认知障碍知识动员中心:分享研究故事
  • 批准号:
    498288
  • 财政年份:
    2024
  • 资助金额:
    $ 49.92万
  • 项目类别:
    Operating Grants
EMNANDI: Advanced Characterisation and Aging of Compostable Bioplastics for Automotive Applications
EMNANDI:汽车应用可堆肥生物塑料的高级表征和老化
  • 批准号:
    10089306
  • 财政年份:
    2024
  • 资助金额:
    $ 49.92万
  • 项目类别:
    Collaborative R&D
関節リウマチ患者のSuccessful Agingに向けたフレイル予防対策の構築
类风湿性关节炎患者成功老龄化的衰弱预防措施的建立
  • 批准号:
    23K20339
  • 财政年份:
    2024
  • 资助金额:
    $ 49.92万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Baycrest Academy for Research and Education Summer Program in Aging (SPA): Strengthening research competencies, cultivating empathy, building interprofessional networks and skills, and fostering innovation among the next generation of healthcare workers t
Baycrest Academy for Research and Education Summer Program in Aging (SPA):加强研究能力,培养同理心,建立跨专业网络和技能,并促进下一代医疗保健工作者的创新
  • 批准号:
    498310
  • 财政年份:
    2024
  • 资助金额:
    $ 49.92万
  • 项目类别:
    Operating Grants
Life course pathways in healthy aging and wellbeing
健康老龄化和福祉的生命历程路径
  • 批准号:
    2740736
  • 财政年份:
    2024
  • 资助金额:
    $ 49.92万
  • 项目类别:
    Studentship
I-Corps: Aging in Place with Artificial Intelligence-Powered Augmented Reality
I-Corps:利用人工智能驱动的增强现实实现原地老龄化
  • 批准号:
    2406592
  • 财政年份:
    2024
  • 资助金额:
    $ 49.92万
  • 项目类别:
    Standard Grant
NSF PRFB FY 2023: Connecting physiological and cellular aging to individual quality in a long-lived free-living mammal.
NSF PRFB 2023 财年:将生理和细胞衰老与长寿自由生活哺乳动物的个体质量联系起来。
  • 批准号:
    2305890
  • 财政年份:
    2024
  • 资助金额:
    $ 49.92万
  • 项目类别:
    Fellowship Award
虚弱高齢者のSuccessful Agingを支える地域課題分析指標と手法の確立
建立区域问题分析指标和方法,支持体弱老年人成功老龄化
  • 批准号:
    23K20355
  • 财政年份:
    2024
  • 资助金额:
    $ 49.92万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
「ケア期間」に着目したbiological aging指標の開発
开发聚焦“护理期”的生物衰老指数
  • 批准号:
    23K24782
  • 财政年份:
    2024
  • 资助金额:
    $ 49.92万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了