Acid Sphingomyelinase and Niemann-Pick Disease

酸性鞘磷脂酶和尼曼匹克病

基本信息

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this research is to use our unique mouse models of Types A & B Niemann-Pick disease (NPD) to develop new therapies for this disorder and to uncover novel pathogenic mechanisms. Two aims are proposed. Aim 1: Preclinical Evaluation of Two New Therapies. In the first set of studies we will evaluate a novel enzyme enhancement approach using the heat shock protein, Hsp70. These experiments are based on a recent publication showing that Hsp70 enhanced residual ASM activity and reduced lysosomal pathology in cells from Type A and B NPD patients, a finding that has been supported by new in vivo data obtained since the previous submission. The second set of studies will continue our work aimed at improved delivery of ASM to the lung using ICAM-1. A "proof-of-principle" gene transfer experiment will be undertaken that will use AAV8 vectors to express ASM/ICAM-1 fusion proteins in the livers of NPD mice. Uptake and efficacy of the fusion enzymes in the lung and other clinically important organs will be studied. New in vivo data also has been obtained to demonstrate the feasibility of this approach. Aim 2: Investigation of Novel Pathogenic Mechanisms Leading to ERT-Related Liver Toxicity. Preclinical ERT studies in ASM knockout (ASMKO) mice have shown that administration of recombinant ASM at doses above 5 mg/Kg results in liver bleeding, the release of liver enzymes, and death. We have recently found that sphingosine, not sphingomyelin, is the major accumulating lipid in the livers of these mice, and hypothesize that sphingosine storage is responsible, at least in part, for the ERT-associated toxicity. We will determine the source of accumulating sphingosine by evaluating the expression of ceramidases, sphingosine kinases and sphingosine-1-phosphate lyase in the ASMKO mice, and breed these animals to mice lacking sphingosine kinase-1 to determine the effects on ERT- associated liver toxicity. These results should provide a mechanistic basis for the clinical observations in the mice, and also may lead to new strategies to overcome this toxicity.
描述(由申请人提供): 本研究的总体目标是使用我们独特的A型和B型尼曼-匹克病(NPD)小鼠模型来开发这种疾病的新疗法并揭示新的致病机制。提出了两个目标。目的1:两种新疗法的临床前评价。在第一组研究中,我们将使用热休克蛋白Hsp 70评估一种新的酶增强方法。这些实验基于最近的出版物,该出版物显示Hsp 70增强了A型和B型NPD患者细胞中的残留ASM活性并减少了溶酶体病理,这一发现得到了自上次提交以来获得的新体内数据的支持。第二组研究将继续我们的工作,目的是使用ICAM-1改善ASM向肺部的递送。将进行“原理验证”基因转移实验,该实验将使用AAV 8载体在NPD小鼠的肝脏中表达ASM/ICAM-1融合蛋白。将研究融合酶在肺和其他临床重要器官中的摄取和功效。也已经获得了新的体内数据来证明这种方法的可行性。目的2:研究导致ERT相关肝毒性的新致病机制。ASM敲除(ASMKO)小鼠的临床前ERT研究表明,以高于5 mg/Kg的剂量给予重组ASM会导致肝出血、肝酶释放和死亡。我们最近发现,鞘氨醇,而不是鞘磷脂,是这些小鼠肝脏中主要的脂质积累,并假设鞘氨醇储存是负责的,至少部分,ERT相关的毒性。我们将通过评价ASMKO小鼠中神经酰胺酶、鞘氨醇激酶和鞘氨醇-1-磷酸裂解酶的表达来确定鞘氨醇蓄积的来源,并将这些动物与缺乏鞘氨醇激酶-1的小鼠交配,以确定对ERT相关肝毒性的影响。这些结果将为小鼠的临床观察提供机制基础,也可能导致克服这种毒性的新策略。

项目成果

期刊论文数量(11)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Types A and B Niemann-Pick disease.
  • DOI:
    10.1016/j.ymgme.2016.12.008
  • 发表时间:
    2017-01
  • 期刊:
  • 影响因子:
    3.8
  • 作者:
    Schuchman EH;Desnick RJ
  • 通讯作者:
    Desnick RJ
Consensus recommendation for a diagnostic guideline for acid sphingomyelinase deficiency.
Acid sphingomyelinase modulates the autophagic process by controlling lysosomal biogenesis in Alzheimer's disease.
  • DOI:
    10.1084/jem.20132451
  • 发表时间:
    2014-07-28
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Lee JK;Jin HK;Park MH;Kim BR;Lee PH;Nakauchi H;Carter JE;He X;Schuchman EH;Bae JS
  • 通讯作者:
    Bae JS
New paradigms for the treatment of lysosomal storage diseases: targeting the endocannabinoid system as a therapeutic strategy.
  • DOI:
    10.1186/s13023-021-01779-4
  • 发表时间:
    2021-03-25
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Schuchman EH;Ledesma MD;Simonaro CM
  • 通讯作者:
    Simonaro CM
Inhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signaling.
  • DOI:
    10.15252/emmm.201911776
  • 发表时间:
    2020-11-06
  • 期刊:
  • 影响因子:
    11.1
  • 作者:
    Bartoll A;Toledano-Zaragoza A;Casas J;Guzmán M;Schuchman EH;Ledesma MD
  • 通讯作者:
    Ledesma MD
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EDWARD H. SCHUCHMAN其他文献

EDWARD H. SCHUCHMAN的其他文献

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{{ truncateString('EDWARD H. SCHUCHMAN', 18)}}的其他基金

Endocannabinoid-Based Treatment for the Neurologic Niemann-Pick Diseases
基于内源性大麻素的神经尼曼匹克病治疗
  • 批准号:
    10701903
  • 财政年份:
    2022
  • 资助金额:
    $ 41.53万
  • 项目类别:
Acid Sphingomyelinase and Niemann-Pick Disease
酸性鞘磷脂酶和尼曼匹克病
  • 批准号:
    9247906
  • 财政年份:
    2017
  • 资助金额:
    $ 41.53万
  • 项目类别:
ACID CERAMIDASE, CERAMIDE & FARBER DISEASE
酸性神经酰胺酶、神经酰胺
  • 批准号:
    7992518
  • 财政年份:
    2010
  • 资助金额:
    $ 41.53万
  • 项目类别:
ACID SPHINGOMYELINASE & NIEMANN-PICK DISEASE
酸性鞘磷脂酶
  • 批准号:
    7935121
  • 财政年份:
    2009
  • 资助金额:
    $ 41.53万
  • 项目类别:
CERAMIDASES, CERAMIDE, AND FARBER DISEASE
神经酰胺酶、神经酰胺和法伯病
  • 批准号:
    6342531
  • 财政年份:
    2000
  • 资助金额:
    $ 41.53万
  • 项目类别:
Acid Ceramidase, Ceramide and Farber Disease
酸性神经酰胺酶、神经酰胺和法伯病
  • 批准号:
    8661160
  • 财政年份:
    2000
  • 资助金额:
    $ 41.53万
  • 项目类别:
CERAMIDASES, CERAMIDE, AND FARBER DISEASE
神经酰胺酶、神经酰胺和法伯病
  • 批准号:
    6688273
  • 财政年份:
    2000
  • 资助金额:
    $ 41.53万
  • 项目类别:
Acid Ceramidase, Ceramide and Farber Disease
酸性神经酰胺酶、神经酰胺和法伯病
  • 批准号:
    8035557
  • 财政年份:
    2000
  • 资助金额:
    $ 41.53万
  • 项目类别:
Acid Ceramidase, Ceramide and Farber Disease
酸性神经酰胺酶、神经酰胺和法伯病
  • 批准号:
    8461530
  • 财政年份:
    2000
  • 资助金额:
    $ 41.53万
  • 项目类别:
Acid Ceramidase, Ceramide and Farber Disease
酸性神经酰胺酶、神经酰胺和法伯病
  • 批准号:
    8848063
  • 财政年份:
    2000
  • 资助金额:
    $ 41.53万
  • 项目类别:

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