Huntington's Disease: Learning from Extremes
Huntington's Disease: Learning from Extremes
批准号:
10445001
负责人:
HERMINIA Diana ROSAS
金额:
$151.67万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-09-15 至 2024-06-30
关键词:
AdolescentAgeAge of OnsetAnimalsAtrophicAutopsyBiological FactorsBiological MarkersBiological ModelsBiologyBloodChildhoodClinicalClinical TrialsCognitiveConduct Clinical TrialsDNADNA Sequence AlterationData SetDevelopmentDiseaseEnrollmentEnvironmental Risk FactorGenderGenesGeneticGenomicsGoalsHumanHuntington DiseaseHuntington proteinImageImage AnalysisImpaired cognitionIndividualLate-Onset Huntington DiseaseLearningLengthLifeLongevityMagnetic Resonance ImagingMeasuresMethodsModificationMolecularMotorNeuraxisNeurodegenerative DisordersNeuropsychologyOther GeneticsPathogenesisPathway interactionsPatientsPhenotypePlasmaRNASeverity of illnessSpan 40Stratification FactorsTestingTherapeuticTissuesValidationVariantbasecerebral atrophycohortdesignearly onsetexperimental studyfallsgenome wide association studyillness lengthmetabolomicsmotor disordermutantneuroimagingpatient variabilitypersonalized approachprogression markerprotein biomarkersrate of changerecruitsmall moleculetherapeutic targettranscriptome sequencingtranscriptomics
中文摘要
亨廷顿病:从极端中学习
摘要:亨廷顿病(HD)是一种以进行性神经退行性疾病为特征的致死性遗传性疾病
运动、精神和认知能力下降。 它是由基因突变导致的全球细胞
突变亨廷顿蛋白(mtHtt)的表达,这是特别有毒的中枢神经系统。 疾病改善
这种毁灭性和致命的疾病还没有治疗方法。 设计的挑战之一
有效的临床试验是观察到的巨大的临床变异性。 大部分的可变性都包含在
受试者之间的进展速度明显不同,这可能是由遗传和
环境因素CAG扩张长度不能解释可变进展,因为绝大多数
的HD患者的CAG长度范围有限,介于41- 47岁之间,但临床发病年龄为
从童年到生命的第八个十年。全基因组关联研究(GWAS)已经揭示了一些潜在的
其他基因的贡献非常有限,不能解释临床观察到的极端情况。 我们有
研究了CAGn和疾病持续时间相匹配的、早发和迟发的非复发性青少年HD受试者,
发现早期发病与更快的脑萎缩相关,而老年发病与更慢的脑萎缩相关,
提示发病年龄是进展斜率的强预测因子。 了解生物学
不同发病年龄和进展速度的基础因素可能揭示了相关性,
了解和预测进展率,并可能有助于确定新的治疗目标。 我们有
先前在血液和HD受试者中发现的代谢组学、遗传学和转录组学标志物改变
代表了可能影响疾病进展的途径。 我们建议扩大我们的早期和晚期队列,
发病的受试者,评估他们的进展临床和神经影像学,并进行公正和
对血液和脑脊液标志物进行有针对性的研究,以寻找进展差异的区别线索。
英文摘要
Huntington’s disease: Learning from Extremes
Abstract: Huntington's disease (HD) is a fatal genetic neurodegenerative disorder characterized by progressive
motor, psychiatric and cognitive decline. It is caused by a genetic mutation leading to the global cellular
expression of the mutant huntingtin protein (mtHtt), which is particularly toxic to the CNS. Disease modifying
treatments are not yet available for this devastating and lethal disease. One of the challenges for designing
efficient clinical trials is the tremendous clinical variability that is observed. Much of that variability is contained
in the markedly different rates of progression between subjects, which are likely caused by both genetic and
environmental factors. Variable progression is not explained by the CAG expansion length since the vast majority
of individuals with HD fall in a limited range of CAG lengths spanning 41-47 yet have ages of clinical onset from
childhood to the 8th decade of life. Genome-wide association studies (GWAS) have uncovered some potential
and very limited contributions from other genes and do not explain the extremes observed clinically. We have
studied non-juvenile HD subjects matched for CAGn and disease duration and having early and late onset and
find that earlier onset is associated with more rapid cerebral atrophy and older onset with slower cerebral atrophy,
suggesting that age-of-onset is a strong predictor of the slope of progression. Understanding the biological
factors that underlie divergent ages of onset and rates of progression may uncover correlates that enable
understanding and predicting rates of progression and may help identify new treatment targets. We have
previously identified altered metabolomic, genetic, and transcriptomic markers from the blood and in HD subjects
that represent pathways that could influence progression. We propose to expand our cohort of early and late
onset subjects, evaluate their progression clinically and by neuroimaging, and to perform both unbiased and
targeted studies of blood and csf markers to seek distinguishing clues to the variance in progression.
期刊论文(4)
专著(0)
科研奖励(0)
会议论文
Association of Dilated Perivascular Spaces and Disease Severity in Patients With Huntington Disease.
DOI:
10.1212/wnl.0000000000011121
发表时间:
2021-02-09
期刊:
Neurology
影响因子:
9.9
作者:
[Chan ST, Mercaldo ND, Ravina B, Hersch SM, Rosas HD]
通讯作者:
Rosas HD
Electrocardiogram Abnormalities Suggest Aberrant Cardiac Conduction in Huntington's Disease.
心电图异常表明亨廷顿舞蹈病的心脏传导异常。
DOI:
10.1002/mdc3.12596
发表时间:
2018
期刊:
Movement disorders clinical practice
影响因子:
4
作者:
[Stephen,ChristopherD, Hung,Judy, Schifitto,Giovanni, Hersch,StevenM, Rosas,HDiana]
通讯作者:
Rosas,HDiana
DOI:
10.3389/fphys.2021.663898
发表时间:
2021
期刊:
Frontiers in physiology
影响因子:
4
作者:
[Chan ST, Mercaldo ND, Kwong KK, Hersch SM, Rosas HD]
通讯作者:
Rosas HD
Understanding the contribution of altered cerebrovascular function to the pathology and clinical symptoms of Huntington disease
-
批准号:10314055
-
项目类别:
-
资助金额:$66.85万
-
财政年份:2020
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
Understanding the Contribution of Altered Cerebrovascular Function to the Pathology and Clinical Symptoms of Huntington Disease
-
批准号:10708843
-
项目类别:
-
资助金额:$66.85万
-
财政年份:2020
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
Huntington's Disease: Learning from Extremes
-
批准号:10216367
-
项目类别:
-
资助金额:$151.67万
-
财政年份:2018
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
Using High Field MRI to Evaluate Metal Dyshomeostasis in Huntington???s Disease
-
批准号:8584115
-
项目类别:
-
资助金额:$26.1万
-
财政年份:2013
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
Using High Field MRI to Evaluate Metal Dyshomeostasis in Huntington???s Disease
-
批准号:8670040
-
项目类别:
-
资助金额:$21.53万
-
财政年份:2013
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
CLINICAL TRIAL: CREST-X
-
批准号:7731259
-
项目类别:
-
资助金额:$0.28万
-
财政年份:2008
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
CREST-X
-
批准号:7607071
-
项目类别:
-
资助金额:$0.74万
-
财政年份:2006
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
NOVEL BIOMARKERS IN HUNTINGTON'S DISEASE
-
批准号:7607049
-
项目类别:
-
资助金额:$0.03万
-
财政年份:2006
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
OPEN-LABEL FOLLOW-UP STUDY OF PHENYLBUTYRATE IN HD
-
批准号:7607070
-
项目类别:
-
资助金额:$1.38万
-
财政年份:2006
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
CREST-X
-
批准号:7374763
-
项目类别:
-
资助金额:$1.23万
-
财政年份:2005
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
OPEN-LABEL FOLLOW-UP STUDY OF PHENYLBUTYRATE IN HD
-
批准号:7374762
-
项目类别:
-
资助金额:$2.34万
-
财政年份:2005
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
CREST-UP1
-
批准号:7205104
-
项目类别:
-
资助金额:$1.29万
-
财政年份:2004
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
Prospective Neuroimaging in Huntington's Disease
-
批准号:6683022
-
项目类别:
-
资助金额:$38.66万
-
财政年份:2003
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
Prospective Neuroimaging in Huntington's Disease
-
批准号:8260536
-
项目类别:
-
资助金额:$72.39万
-
财政年份:2003
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
Prospective Neuroimaging in Huntington's Disease
-
批准号:8457059
-
项目类别:
-
资助金额:$70.7万
-
财政年份:2003
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
Prospective Neuroimaging in Huntington's Disease
-
批准号:6924624
-
项目类别:
-
资助金额:$41.09万
-
财政年份:2003
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
Prospective Neuroimaging in Huntington's Disease
-
批准号:7087789
-
项目类别:
-
资助金额:$40.12万
-
财政年份:2003
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
Prospective Neuroimaging in Huntington's Disease
-
批准号:8061582
-
项目类别:
-
资助金额:$72.49万
-
财政年份:2003
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
Prospective Neuroimaging in Huntington's Disease
-
批准号:7271881
-
项目类别:
-
资助金额:$38.96万
-
财政年份:2003
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
Prospective Neuroimaging in Huntington's Disease
-
批准号:7914104
-
项目类别:
-
资助金额:$71.77万
-
财政年份:2003
-
负责人:HERMINIA Diana ROSAS
-
依托单位:
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