课题基金 / 基金详情

Restoration of proteostasis to address co-occurring conditions in Down Syndrome

Restoration of proteostasis to address co-occurring conditions in Down Syndrome
恢复蛋白质稳态以解决唐氏综合症的并发病症
批准号:
10518555
负责人:
NIRMALA NIRINJINI NAIDOO
金额:
$185.63万
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
项目状态:
未结题
起止时间:
2022-09-15 至 2025-08-31

项目摘要

项目成果

NIRMALA NIRINJINI NAIDOO的其他基金

相似基金

相关文献

中文摘要
翻译
摘要 患有唐氏综合症(DS)的人寿命缩短,随着年龄的增长面临严峻的挑战。而 原发性综合征是由21号染色体的额外拷贝引起的,从出生时就存在, 患睡眠和代谢紊乱的风险要高得多,超过三分之二的人 经历类似于早发性阿尔茨海默病(AD)的认知能力下降。没有统一 机制或方法来治疗这些共同发生的条件,这可能会导致急剧恶化, 生活质量已发表的和初步的数据表明,受损的蛋白质稳态和异常激活的 蛋白质稳态途径,即未折叠蛋白反应(UPR),是AD常见的生物学机制, 睡眠和代谢功能障碍。此外,蛋白质折叠应激可以是染色体断裂的直接后果。 来自人类和小鼠的数据支持DS中异常UPR诱导的概念。因此我们 提出DS患者易受蛋白质折叠应激的影响,恢复蛋白质稳态是一种治疗方法。 新的治疗方法,以防止共同发生的条件。我们认为,减少蛋白酶抑制剂 压力通过化学伴侣4-苯基丁酸酯(PBA)-一种小的饱和脂肪酸,是FDA- 批准的用于治疗尿素循环障碍的疗法-将反过来改善睡眠障碍, 新陈代谢和认知。淀粉样前体蛋白(APP)是家族性AD的关键分子,是三重蛋白之一。 基因在DS淀粉样β(Aβ)肽的过度表达和随之而来的过度生产导致 在DS人群中AD神经病理学的早期发作中起作用的蛋白毒性。我们发现 用PBA处理的APP敲入(APPKI)小鼠显示出减少的蛋白毒性应激和改善的认知能力, 行为,即使在认知能力下降开始后开始治疗。我们的数据还表明,PBA 改善APPKI和正常衰老小鼠的睡眠质量。此外,一些已发表的研究表明,PBA 恢复肥胖小鼠的代谢功能。因此,这一提议的总体假设是, 与FDA批准的小分子伴侣PBA的蛋白质抑制应激将改善睡眠, 代谢和行为缺陷的小鼠模型的DS。我们将使用经验证的DS Ts 65 Dn小鼠 一个三体模型,大约三分之二的基因与人类21号染色体正交,并显示每个 的相关表型,以测试PBA治疗是否挽救这些共同发生的条件。这 该提案建立在现有文献和新的初步数据的基础上,这些文献和数据支持PBA的潜力, 一种FDA批准的治疗方法,用于改善认知能力下降、睡眠障碍和代谢功能障碍。作为 这些条件共同发生在唐氏综合症的个人,这个项目是一个关键的第一步, 开发统一的治疗方法。
英文摘要
ABSTRACT Individuals with Down syndrome (DS) have shortened lifespan and face severe challenges as they age. While the primary syndrome is caused by an extra copy of chromosome 21, and is present from birth, those with DS are at a much higher risk of developing sleep and metabolic disorders and more than two thirds of individuals experience cognitive decline that resembles early-onset Alzheimer's disease (AD). There is no unified mechanism or approach to treating these co-occurring conditions, which can lead to a drastic deterioration in quality of life. Published and preliminary data indicate that impaired proteostasis and aberrant activation of the proteostasis pathway, the unfolded protein response (UPR), is a biological mechanism common to AD, disrupted sleep and metabolic dysfunction. Moreover, protein folding stress can be a direct consequence of chromosome imbalance and data from humans and mice support the concept of aberrant UPR induction in DS. Thus, we propose that individuals with DS are susceptible to protein folding stress and that restoring proteostasis is a novel therapeutic approach to prevent co-occurring conditions. We posit that reducing proteostatic stress via chemical chaperone 4-phenyl butyrate (PBA) – a small saturated fatty acid that is an FDA- approved therapy for treatment of urea cycle disorders – will in turn ameliorate disturbances in sleep, metabolism, and cognition. Amyloid precursor protein (APP), a key player in familial AD, is one of the triplicated genes in DS. Overexpression and the consequent overproduction of amyloid beta (Aβ)-peptide leads to proteotoxicity that is instrumental in the early onset of AD neuropathology in the DS population. We have found that APP knockin (APPKI) mice treated with PBA display reduced proteotoxic stress and improved cognitive behavior, even when treatment was initiated after the onset of cognitive decline. Our data also indicate that PBA improves sleep quality in APPKI and normally aging mice. Moreover, several published studies indicate that PBA restores metabolic function in obese mice. Therefore, the global hypothesis of this proposal is that reduction of proteostatic stress with the FDA-approved small molecule chaperone PBA will ameliorate sleep, metabolic and behavioral deficits in a mouse model of DS. We will use the validated DS Ts65Dn mouse model that is trisomic for about two-thirds of the genes orthologous to human chromosome 21 and displays each of the relevant phenotypes to test whether PBA treatment rescues each of these co-occurring conditions. This proposal builds on a strong body of existing literature and new preliminary data supporting the potential of PBA, an FDA-approved therapy, for improving cognitive decline, sleep disturbances, and metabolic dysfunction. As these conditions co-occur in individuals with Down syndrome, this project represents a crucial first step towards developing a unified therapeutic approach.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Interactions between the immune response and lipid homeostasis in regulating sleep during sickness
  • 批准号:
    10634707
  • 项目类别:
  • 资助金额:
    $48.56万
  • 财政年份:
    2022
  • 负责人:
    NIRMALA NIRINJINI NAIDOO
  • 依托单位:
Cellular and Molecular Basis of Sleep Loss Neural Injury in Alzheimer Disease
  • 批准号:
    10586062
  • 项目类别:
  • 资助金额:
    $73.12万
  • 财政年份:
    2020
  • 负责人:
    NIRMALA NIRINJINI NAIDOO
  • 依托单位:
Cellular and Molecular Basis of Sleep Loss Neural Injury in Alzheimer Disease
  • 批准号:
    10373983
  • 项目类别:
  • 资助金额:
    $73.12万
  • 财政年份:
    2020
  • 负责人:
    NIRMALA NIRINJINI NAIDOO
  • 依托单位:
Mechanisms of Cellular Stress-Induced Sleep
  • 批准号:
    9175443
  • 项目类别:
  • 资助金额:
    $33.01万
  • 财政年份:
    2016
  • 负责人:
    NIRMALA NIRINJINI NAIDOO
  • 依托单位:
国内基金
海外基金
补阳还五汤通过AGE-RAGE通路调控脓毒症免疫失衡的机制与转化研究
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
  • 批准号:
    JCZRQN202500010
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2025
  • 负责人:
  • 依托单位:
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
  • 批准号:
    2025JJ70209
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2025
  • 负责人:
    雷芬芳
  • 依托单位:
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
  • 批准号:
    --
  • 项目类别:
    面上项目
  • 资助金额:
    --
  • 批准年份:
    2024
  • 负责人:
    万荣
  • 依托单位: