MOLEC PATHOPHYS OF CLIN VARIATION IN SPINAL CORD DISEASE
脊髓疾病临床变异的分子病理学
基本信息
- 批准号:6394444
- 负责人:
- 金额:$ 24.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2000
- 资助国家:美国
- 起止时间:2000-09-29 至 2002-08-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (Applicant's abstract): Many, if not most, central nervous system
disorders show clinical variability between patients. Even in inherited
disorders where a cohort of patients can share the same genetic and biochemical
lesion, patients will show clinically discordant phenotypes. Here, we propose
to investigate the molecular basis for clinical variability with identical
genetic lesions and genetic backgrounds using expression profiling of mouse
spasticity models. Spasticity is a common neurological symptom that can reflect
damage to the brain or spinal cord, or can reflect any one of a series of
inbred biochemical defects. Mouse models of inherited spasticity fall into two
recessive linkage groups. One group is due to loss-of-function mutations of the
alpha 1 subunit of the inhibitory glycine receptor, while the second group is
due to loss-of-function mutations of the beta subunit. Two alleles of these
mutants, spastic and spasmodic, are particularly interesting in their
progression of the disorder. Affected homozygotes show normal birth and early
development, but then develop a progressive spastic phenotype by 3 to 5 weeks
of age. After this time, the phenotype is variable, with some mice showing
clinical improvement of the spasticity, while littermates can show significant
worsening with age. This clinical variability is despite the identical
mutation, in the same inbred genetic background.
Our hypothesis is that critical differences in pathophysiological cascades arc
occurring in clinically discordant littermates. We propose that these
differences can be identified by expression profiling of spinal cords of
affected mice. The identification of consistent expression changes associated
with clinical worsening or clinical improvement of spasticity will identify key
pathways amenable to drug modulation. We hypothesize that the drug targets
identified by this expression profiling approach could prove useful in all
spasticity syndromes, and possibly in improving spinal cord recovery from
damage. Our laboratory at the Children's National Medical Center is fully
equipped for expression profiling by both cDNA arrays, and Affymetrix
technologies. We show preliminary data on expressing profiling of the spastic
mouse spinal cord relative to normal controls using Affymetrix stock chips,
which identify both expected, and unexpected changes. This research proposal
has two aims; in the first, we will conduct Affymetrix expression profiling in
a limited series of mouse spinal cords, using both spastic (alpha 1 subunit
deficiency) and spasmodic (beta subunit deficiency) mice. We will then produce
custom cDNA arrays of all genes showing "dif" calls, and perform a series of
expression profiling experiments on discordant littermates. Comparison of the
genes showing consistent dif calls in discordant littermates by the cDNA
microarrays should identify important pathological cascades that play a role in
dictating clinical severity. Our findings should have significance for the
progression of inherited forms of spastic paraplegia but also more broadly for
spinal cord injury and CNS homeostasis.
描述(申请人摘要):许多(如果不是大多数)中枢神经系统
疾病显示患者之间的临床变异性。即使在继承
一组患者可以共享相同的遗传和生化特征的疾病
病变,患者将显示临床上不一致的表型。在此,我们建议
为了研究具有相同的临床变异性的分子基础,
使用小鼠的表达谱的遗传病变和遗传背景
痉挛模型痉挛是一种常见的神经症状,
大脑或脊髓损伤,或者可以反映一系列
近亲繁殖的生化缺陷遗传性痉挛的小鼠模型分为两种
隐性连锁群一组是由于基因组的功能丧失突变,
抑制性甘氨酸受体的α 1亚基,而第二组是
这是由于β亚基的功能丧失突变。其中两个等位基因
突变体,痉挛和痉挛,是特别有趣的,在他们的
疾病的进展。受影响的纯合子显示正常出生和早期
发育,但随后在3至5周时发展为进行性痉挛表型
年龄。此后,表型发生变化,一些小鼠表现出
痉挛状态的临床改善,而同窝仔可表现出显著的
随着年龄的增长而恶化。这种临床变异性是尽管相同
突变,在相同的近交遗传背景下。
我们的假设是,病理生理级联反应的关键差异是
发生在临床上不一致的同窝仔中。我们建议,这些
差异可以通过脊髓的表达谱来鉴定,
受影响的老鼠鉴定与此相关的一致表达变化
痉挛的临床恶化或临床改善将确定关键
药物调节的途径。我们假设药物靶向
通过这种表达谱分析方法确定的基因可以证明在所有
痉挛综合征,并可能在改善脊髓恢复,
损害我们在儿童国家医疗中心的实验室完全
配备用于cDNA阵列和Affyphase表达谱分析的设备,
技术.我们展示了痉挛性脊髓炎表达谱的初步数据,
小鼠脊髓相对于正常对照使用Affyestivalstockchips,
其识别预期的和未预期的变化。本研究提案
有两个目标;首先,我们将在
一系列有限的小鼠脊髓,使用痉挛(α 1亚单位)
缺乏)和痉挛(β亚单位缺乏)小鼠。我们将生产
所有显示“dif”调用的基因的定制cDNA阵列,并执行一系列
对不一致同窝出生的小鼠进行表达谱分析实验。比较
在不一致的同窝仔中显示一致差异呼叫的基因,
微阵列应该识别重要的病理级联反应,
指示临床严重性。我们的发现应该对
遗传性痉挛性截瘫的进展,但也更广泛地为
脊髓损伤和中枢神经系统稳态。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ERIC P. HOFFMAN其他文献
Proteolytic fragment or new gene product?
蛋白水解片段还是新基因产物?
- DOI:
10.1038/336210a0 - 发表时间:
1988-11-01 - 期刊:
- 影响因子:48.500
- 作者:
ERIC P. HOFFMAN;LOUIS M. KUNKEL;ROBERT H. BROWN - 通讯作者:
ROBERT H. BROWN
ERIC P. HOFFMAN的其他文献
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{{ truncateString('ERIC P. HOFFMAN', 18)}}的其他基金
Clinical Trial Readiness for Monitoring Muscle Inflammation in Duchenne Muscular Dystrophy
监测杜氏肌营养不良症肌肉炎症的临床试验准备
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10725465 - 财政年份:2023
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Commercialization Readiness Pilot (CRP) to maximize vamorolone international labeling and sales
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- 批准号:
10200153 - 财政年份:2016
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K12 Career Development Program: Omics of Pediatric Lung Diseases in DC
K12 职业发展计划:华盛顿特区小儿肺部疾病组学
- 批准号:
8857246 - 财政年份:2013
- 资助金额:
$ 24.42万 - 项目类别:
K12 Career Development Program: Omics of Pediatric Lung Diseases in DC
K12 职业发展计划:华盛顿特区小儿肺部疾病组学
- 批准号:
8722615 - 财政年份:2013
- 资助金额:
$ 24.42万 - 项目类别:
K12 Career Development Program: Omics of Pediatric Lung Diseases in DC
K12 职业发展计划:华盛顿特区小儿肺部疾病组学
- 批准号:
8575197 - 财政年份:2013
- 资助金额:
$ 24.42万 - 项目类别:
Center for Research Translation of Systemic Exon-skipping in Muscular Dystrophy
肌营养不良症系统性外显子跳跃研究转化中心
- 批准号:
8544772 - 财政年份:2011
- 资助金额:
$ 24.42万 - 项目类别:
Center for Research Translation of Systemic Exon-skipping in Muscular Dystrophy
肌营养不良症系统性外显子跳跃研究转化中心
- 批准号:
8330812 - 财政年份:2011
- 资助金额:
$ 24.42万 - 项目类别:
Center for Research Translation of Systemic Exon-skipping in Muscular Dystrophy
肌营养不良症系统性外显子跳跃研究转化中心
- 批准号:
8734214 - 财政年份:2011
- 资助金额:
$ 24.42万 - 项目类别:
Center for Research Translation of Systemic Exon-skipping in Muscular Dystrophy
肌营养不良症系统性外显子跳跃研究转化中心
- 批准号:
8090706 - 财政年份:2011
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AN EXERCISE INTERVENTION IN INSULIN-RESISTANT MINORITY ADOLESCENTS
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