Neurotoxicity of Spermine Synthase-deficiency and Polyamine Imbalance

精胺合酶缺乏和多胺失衡的神经毒性

基本信息

  • 批准号:
    10752966
  • 负责人:
  • 金额:
    $ 112.85万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-14 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

Title: Neurotoxicity of Spermine Synthase-Deficiency and Polyamine Imbalance PI: R. Grace Zhai, PhD, University of Miami School of Medicine, Miami, FL Co-I: Rich Steet, PhD, Greenwood Genetic Center, Greenwood, SC Co-I: Luigi Boccuto, MD, Clemson University School of Nursing, Clemson, SC PROJECT SUMMARY Polyamines, namely spermidine, spermine, and their precursor putrescine are tightly regulated polycations essential for life. First indications linking polyamine metabolism and neurological disorders came from the observations of abnormal polyamine levels accompanying several brain injury conditions including ischemic brain damage and traumatic brain injury. The pivotal role of polyamine metabolism emerged with the mapping of causal mutation of Snyder-Robinson Intellectual Disability Syndrome (SRS, OMIM 309583) to spermine synthase (SMS), an enzyme that catalyzes the conversion of spermidine to spermine. Our work in the previous grant cycle (R01 NS109640) investigated the pathological consequence of polyamine imbalance in the nervous system in the context of SRS. We have established a Drosophila model for SRS to recapitulate several key features of SRS pathology, have uncovered altered redox state, dysregulated protein acetylation, and lysosomal dysfunction as primary neurotoxicity underlying SRS pathology, and most importantly, have identified phenylbutyrate (PBA) as a robust pharmacological suppressor of neurotoxicity in SRS in vivo models and in patient cells. Recently, we made the exciting discovery of the critical connection between polyamine metabolism and Tau aggregation-induced neurodegeneration. Specifically, we found that while complete loss of SMS causes SRS, partial loss of SMS (SMS+/-, carriers) showed resistance to Tau-induced neurodegeneration in Tauopathy models. This finding has two important implications: first, polyamines may regulate Tau aggregational toxicity; and second, progression of neurodegeneration in Tauopathy could be delayed by modulating polyamine metabolism. Our objectives for this renewal application are to establish the mechanistic link between polyamine metabolism and Tau/amyloid aggregational neurotoxicity, and identify neuroprotective strategies based on modulating polyamine metabolism using complementary model systems; 1) in vivo Drosophila models, 2) human fibroblasts cells from SRS patients (male, SMS-/y) and heterozygous carriers (female, SMS+/-), and 3) gene expression analyses of human Alzheimer’s Disease related dementia (ADRD) datasets. We hypothesize that modulating polyamine metabolism and shifting spermine/spermidine ratio enhances autophagic flux, regulates global acetylation landscape, facilitates the clearance of toxic Tau/amyloid oligomer species, and confers resistance to neurodegeneration in proteinopathy. We propose to define metabolic and cellular mechanisms underlying SMS+/- mediated neuroprotection against Tau/amyloid accumulation-induced neurodegeneration in vivo in Drosophila (Aim 1); characterize autophagic flux and proteostasis in human primary cells of SRS patient (male, SMS-/y), carriers (female, SMS-/+), and controls (+/+) (Aim 2); and carry out analysis of ADRD RNAseq and protein expression datasets to identify polyamine dysregulation risk factors and metabolic targets for neuroprotection against ADRD (Aim 3). The proposed research will reveal novel chemical and molecular connection between polyamine metabolism and global protein homeostasis, and more importantly reveal a previously unexplored therapeutic direction for AD pathogenesis.
题目:精胺合酶缺乏和多胺失衡的神经毒性

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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Rong Grace Zhai其他文献

Rong Grace Zhai的其他文献

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{{ truncateString('Rong Grace Zhai', 18)}}的其他基金

microRNA regulation of NMNAT-mediated Neuroprotection against Peripheral Neuropathy and Chronic Pain
NMNAT 介导的针对周围神经病变和慢性疼痛的神经保护的 microRNA 调节
  • 批准号:
    10704161
  • 财政年份:
    2019
  • 资助金额:
    $ 112.85万
  • 项目类别:
microRNA regulation of NMNAT-mediated Neuroprotection against Peripheral Neuropathy and Chronic Pain
NMNAT 介导的针对周围神经病变和慢性疼痛的神经保护的 microRNA 调节
  • 批准号:
    10677059
  • 财政年份:
    2019
  • 资助金额:
    $ 112.85万
  • 项目类别:
microRNA regulation of NMNAT-mediated Neuroprotection against Peripheral Neuropathy and Chronic Pain
NMNAT 介导的针对周围神经病变和慢性疼痛的神经保护的 microRNA 调节
  • 批准号:
    10879437
  • 财政年份:
    2019
  • 资助金额:
    $ 112.85万
  • 项目类别:
Neurotoxicity of Spermine Synthase-deficiency and Polyamine Imbalance
精胺合酶缺乏和多胺失衡的神经毒性
  • 批准号:
    10445331
  • 财政年份:
    2018
  • 资助金额:
    $ 112.85万
  • 项目类别:
Neurotoxicity of Spermine Synthase-deficiency and Polyamine Imbalance
精胺合酶缺乏和多胺失衡的神经毒性
  • 批准号:
    10015358
  • 财政年份:
    2018
  • 资助金额:
    $ 112.85万
  • 项目类别:
Neurotoxicity of Spermine Synthase-deficiency and Polyamine Imbalance
精胺合酶缺乏和多胺失衡的神经毒性
  • 批准号:
    10242802
  • 财政年份:
    2018
  • 资助金额:
    $ 112.85万
  • 项目类别:
Mechanisms of Neuronal Maintenance and Protection.
神经元维持和保护机制。
  • 批准号:
    8489360
  • 财政年份:
    2009
  • 资助金额:
    $ 112.85万
  • 项目类别:
Mechanisms of Neuronal Maintenance and Protection.
神经元维持和保护机制。
  • 批准号:
    7737404
  • 财政年份:
    2009
  • 资助金额:
    $ 112.85万
  • 项目类别:
Mechanisms of Neuronal Maintenance and Protection.
神经元维持和保护机制。
  • 批准号:
    8269077
  • 财政年份:
    2009
  • 资助金额:
    $ 112.85万
  • 项目类别:
Mechanisms of Neuronal Maintenance and Protection.
神经元维持和保护机制。
  • 批准号:
    8097985
  • 财政年份:
    2009
  • 资助金额:
    $ 112.85万
  • 项目类别:
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