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Genetic analyses of cerebellar malformations

小脑畸形的遗传分析

基本信息

批准号：
7572904
负责人：
Ian Amos Glass
金额：
$ 10.26万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7572904
关键词：
Ataxia Biochemical Blood specimen Brain Stem Brain imaging Candidate Disease Gene Cephalic Cerebellar malformation Cerebellar vermis structure Cerebellum Cerebral Palsy Cerebrum Chromosomal Rearrangement Chromosome Mapping Classification Clinical Clinical Data Clinical Research Clinical Trials Collection Coloboma Complex Congenital cerebellar hypoplasia Consanguinity DNA Dandy-Walker Syndrome Development Developmental Delay Disorders Developmental Process Diagnosis Disease Dysplasia Eye Movements Faculty Family Future Genes Genetic Genomics Grouping Healthcare Human Image Individual Informed Consent Inherited Joubert syndrome Kidney Kidney Diseases Link Lobe MRI Scans Magnetic Resonance Imaging Maps Medical History Mentors Methods Molar tooth Molecular Molecular Analysis Molecular Genetics Muscle hypotonia Neonatal Nephronophthisis Patients Pattern Phenotype Polydactyly Pontine structure Posterior Fossa Prenatal Diagnosis Radiologic Finding Recommendation Recurrence Research Retinal Dystrophy Risk Role Sampling Surveys Syndrome base career cohort craniofacial developmental disease diagnostic accuracy disease classification genetic analysis genetic pedigree genome wide association study hindbrain improved insight malformation member molecular pathology neuropsychological novel oculomotor patient oriented research permanent cell line relating to nervous system respiratory

项目摘要

DESCRIPTION (provided by applicant): Abnormalities of the human hindbrain are present in Joubert syndrome and closely related cerebello-ocular-renal syndromes, and other often poorly classified cerebellar malformation disorders. Although these disorders are clinically diverse and genetically heterogeneous, they are now more accurately and reliably identified by cranial MRI scanning. However, the genetic, biochemical, and pathophysiological bases of such malformations remains largely unknown. The purpose of this project is to identify genes responsible for Joubert syndrome, Joubert syndrome-related disorders, and other cerebellar-hindbrain malformations in order to gain insights into the normal development and function of the cerebellum. In this application, the candidate will undertake patient-oriented research and mentor trainee/junior faculty members to facilitate research into the basis of human cerebellar malformations. The specific objectives are to clarify the clinical features and spectrum of this complex group of disorders by improved ascertainment with refined clinical studies to enhance diagnostic accuracy as a prelude to gene identification. The candidate intends to gain insight into the molecular basis of these hindbrain malformations by evaluating candidate genes suggested from: (i) a causative role for an overlapping or allelic disorder; (ii) disease associated chromosomal rearrangements; (iii) integrated phenotyping and genetic mapping in cerebellar developmental disorders utilizing consanguineous pedigrees. By these means, the candidate intends to derive logical correlations between the underlying molecular pathology and the features of these disorders. Identification of causal genes for such malformations would provide insights into aberrant cerebellar developmental processes, which result in hindbrain malformations. In addition, the identification of such genes in conjunction with improved clinical nosology would enhance the accuracy of biomedical diagnosis, provide precise recurrence risks to families, and potentially generate options for early prenatal diagnosis. Furthermore, accurate diagnosis by these methods would provide the basis for longitudinal clinical studies, improve the quality of information, health care and management recommendations for such individuals and their families and ultimately, improve the prospect for specific therapies.

描述（由申请人提供）：人类后脑异常存在于Joubert综合征和密切相关的小脑-眼-肾综合征，以及其他经常分类不佳的小脑畸形疾病。尽管这些疾病具有临床多样性和遗传异质性，但现在通过颅脑MRI扫描可以更准确、更可靠地识别它们。然而，这种畸形的遗传、生化和病理生理基础仍然很大程度上未知。该项目的目的是确定Joubert综合征、Joubert综合征相关疾病和其他小脑-后脑畸形的基因，以深入了解小脑的正常发育和功能。在此申请中，候选人将承担以患者为导向的研究，并指导实习生/初级教员，以促进对人类小脑畸形基础的研究。具体的目标是澄清临床特征和频谱这一复杂的疾病组通过改进确定与完善的临床研究，以提高诊断的准确性作为基因鉴定的前奏。候选人打算通过评估从以下方面提出的候选基因来深入了解这些后脑畸形的分子基础：(i)重叠或等位基因疾病的致病作用；（ii）与疾病有关的染色体重排；（iii）利用近亲谱系对小脑发育障碍进行综合表型分析和基因定位。通过这些手段，候选人打算推导出潜在的分子病理学和这些疾病的特征之间的逻辑相关性。这种畸形的致病基因的鉴定将提供对异常小脑发育过程的见解，这导致后脑畸形。此外，这些基因的识别与改进的临床分类学相结合，将提高生物医学诊断的准确性，为家庭提供精确的复发风险，并可能为早期产前诊断提供选择。此外，通过这些方法的准确诊断将为纵向临床研究提供基础，提高信息质量，为这些个人及其家庭提供保健和管理建议，并最终改善特定治疗的前景。