Patient Core

患者核心

• 批准号: 7707266
• 负责人: Michael J Guralnick
• 金额: $ 15.28万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7707266
• 关键词: Affect; Alleles; Behavioral; Blood specimen; Brain; CGG repeat; Canada; Cells; Chromatin Structure; Clinic; Clinical; Cognitive; Collaborations; County; Data; Developmental Delay Disorders; Diagnosis; Elements; Emotional; Endocrine; Evaluation; FMR1; FMR1 Gene; FMRP; Family; Family member; Fathers; Female; Fragile X Premutation; Fragile X Syndrome; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Gene Expression; Gene Frequency; Genes; Genetic Counseling; Genetic Transcription; Grant; Human; Individual; Institutes; Italy; Language; Lead; Leadership; Link; Magnetic Resonance Imaging; Measures; Medical; Messenger RNA; Methylation; Mind; Molecular; Molecular Profiling; Mosaicism; Mus; Mutation; Neonatal Screening; Neurobiology; Neurologic; Newborn Infant; Numbers; Oranges; Patient Recruitments; Patients; Pediatric Hospitals; Phenotype; Premature Ovarian Failure; Prevalence; Program Research Project Grants; Publishing; Purpose; Qualifying; RNA; Recruitment Activity; Regulation; Relative (related person); Research; Resources; Sampling; Screening procedure; Source; Specimen; Testing; Transcript; Tremor/Ataxia Syndrome; Variant; Work; autism spectrum disorder; base; brain tissue; clinical phenotype; experience; interest; international center; member; psychologic; research clinical testing; research study; social

Patient recruitment and evaluation is the essential underpinning of the program project grant. It is through recruitment that patients will be identified, enabling us to study specific variations in the molecular phenotype that are needed for all projects. Patients will be recruited from the families of the newborns seen in the Tassone project and additional families that are seen on a regular basis through our fragile X clinic overseen by Dr Randi Hagerman, the overall PI of the UC Davis Component. We will see between 150 and 200 patients per year in this Core. The molecular/clinical findings from such individuals will be used by the other projects, as follows: 1) The Core will be particularly important in providing the clinical and molecular assessment of the extended family members identified through the newborn screening project. Specifically, the Core will carry out cascade testing and all the clinical and molecular assessments described below, thereby providing data for linking the clinical phenotype with the molecular findings. This Core will therefore help the newborn screening component of the program project grant to: 1) assess the molecular mechanisms underlying FXS and premutation involvement, 2) assess how the molecular variations affect the clinical phenotype, and 3) establish the prevalence of fragile X -associated involvement in family members who are seen through the Core to confirm their diagnosis. The frequency of the FMR1 mutations in the newborns will be established by the Tassone project. Based on the published FMR1 allele frequencies, between 150 and 200 patients, (5-6 member per families from a subject identified through the screening) per year will be needed for this project and they will be recruited and evaluated through this Core. 2) Clinical and molecular profiles on methylation mosaicism will be provided to the "methylation" component (Charles Laird, PI) which focuses on the understanding of the origins of mosaicism in cells of individuals with FXS. 3) RNA and cells will be provided to the project focused on understanding the organization and function of transcription control elements at the FMR1 locus. The PI (Tapscott) has identified a new gene, A.BFMR1 (Ladd et al. submitted), overlapping the CGG repeat region of the FMR1 gene in the antisense orientation. The A.SFMR1 expression appears to be CGG dependent, and it is in fact upregulated in individuals with premutation alleles relative to normal, and is not expressed in full mutation alleles. The Core will provide the PI with primary sources (DNA and RNA) from individuals with a full mutation to understand the mechanism and the influence of the FMR1 antisense-transcript on the FMR1 gene expression. In addition, the Core will also provide project specimens from individuals with the premutation, with and without FXTAS, to study the potential contribution of the bidirectional expression of expanded CGG¿CCG repeats to the pathophysiology of FXTAS. This research will lead to a better understanding of chromatin structure and regulation of regional gene expression. 4) Human brain tissues collected during the first years of funding of this Center Grant will be provided to Drs. Morris and Greenough for comparison between mouse and human. Because Dr. Hagerman and Louise Gane have a positive relationship with so many fragile X families, when a family member dies they are usually willing to donate their brains or whole bodies to our research. Therefore, this resource will not only be available to our Fragile X Research Center but will also be made available to others carrying out fragile X research through Dr. Phil Schwartz brain bank in Children's Hospital of Orange County (CHOC), with whom we have collaborated for years (Schwartz, Tassone et al. 2005). 5) Blood samples are also a resource for national and international centers that are collaborating with us. We have also carried out molecular testing for unique and interesting patients from a number of clinical centers nationally and internationally. One example of this is the female with the full mutation from Canada who received her mutation from her father (Zeesman, Zwaigenbaum et al. 2004). Another example is the molecular study performed on premutation carriers in collaboration with Dr. Bagni, from Italy (Tassone, Beilina et al. 2007). The project focusing on screening (Tassone, PI) will be the only clinical component of the research center grant, but there are important molecular components in the hypotheses of this project. The other 4 projects have a primarily molecular and/or neurobiological focus; however, there are aspects of clinical issues of involvement in their hypotheses. The molecular findings related to the recruited patients are critically important for hypotheses contained in these projects and molecular measures will be utilized frequently in the statistical analyses. It has been shown that molecular variations have a significant impact on physical parameters (Tassone, Hagerman et al. 1999; Loesch, Huggins et al. 2004), MRI volumetric findings (Mostofsky, et al. 1998, Moore, et al. 2002;Cohen et al 2006), functional MRI studies (Menon, Kwon et al. 2000), cognitive measures (Kaufmann, Abrams et al. 1999; Tassone, Hagerman et al. 1999; Loesch, Huggins et al. 2004), and emotional functioning and psychological findings (Hessl, Dyer-Friedman et al. 2001; Hessl, Tassone et al. 2005). For example, in the screening project we hypothesize that the molecular variables will have a significant effect on medical/neurological, cognitive, language, behavioral, and social involvement. The Core will contain the following components, each of which is described in detail in Section D: 1. Patient Recruitment 2. Clinical Evaluations 3. Molecular profile characterization

患者招聘和评估是计划项目赠款的重要基础。它是通过 招募患者将被鉴定出来，使我们能够研究分子表型中的特定变化 所有项目都需要。将从在新生儿家族中招募患者 Tassone项目和其他通过我们脆弱的X诊所定期看到的家庭 加州大学戴维斯分校的总体PI Randi Hagerman博士。我们将看到150至200位患者 每年在这个核心中。其他项目将使用此类人的分子/临床发现，因为 以下内容： 1）核心对于提供扩展的临床和分子评估特别重要 家庭成员通过新生儿筛查项目确定。具体而言，核心将执行级联 测试以及下面描述的所有临床和分子评估，从而提供了链接的数据 分子发现的临床表型。因此，此核心将有助于新生儿筛查组成部分 计划项目授予：1）评估FXS和预先享有的分子机制 参与，2）评估分子变异如何影响临床表型，3）建立 通过核心看到的家庭成员的脆弱X相关参与的患病率以确认 他们的诊断。新生儿中FMR1突变的频率将由流苏建立 项目。根据已发表的FMR1等位基因频率，150至200位患者（每人5-6位成员） 该项目每年都需要每年通过筛选确定的主题的家庭，他们将是 通过此核心招募和评估。 2）将向“甲基化”成分提供甲基化镶嵌化的临床和分子特征 （Charles Laird，pi）的重点是对具有镶嵌物的起源的理解 FXS。 3）RNA和细胞将被提供给专注于了解组织和功能的项目 FMR1基因座的转录控制元件。 PI（Tapscott）已确定了一个新基因A.BFMR1（LADD 等。提交），在反义方向中重叠FMR1基因的CGG重复区域。 a.sfmr1表达似乎取决于CGG，实际上它在患有 相对于正常等位基因，并且不在全突变等位基因中表达。核心将提供PI 来自具有完全突变的个体的主要来源（DNA和RNA），以了解机制和 FMR1反义转录对FMR1基因表达的影响。此外，核心也将 提供有和没有FXTA的人的个人的项目标本，以研究 扩展CGG ccg重复重复的双向表达对病理生理学的潜在贡献 fxtas。这项研究将使对区域基因的染色质结构和调节有更好的了解 表达。 4）将向博士提供该中心赠款的第一年收集的人类脑组织。 莫里斯和绿色，以比较小鼠和人之间。因为哈格曼博士和路易丝·盖恩 与许多脆弱的X家庭有积极的关系，当家庭成员去世时，他们通常愿意 将他们的大脑或整个身体捐赠给我们的研究。因此，此资源不仅可以用于我们的 脆弱的X研究中心，但也将向其他人提供通过Dr.进行脆弱X研究的其他人。 我们与之合作 多年（Schwartz，Tassone等，2005）。 5）血液样本也是与我们合作的国家和国际中心的资源。我们 还对来自许多临床中心的独特且有趣的患者进行了分子测试 在国内和国际上。一个例子是女性，来自加拿大的全部突变 从父亲那里收到了她的突变（Zeesman，Zwaigenbaum等，2004）。另一个例子是分子 研究与来自意大利的Bagni博士合作进行了预先携带的研究（Tassone，Beilina等。 2007）。 关注筛查的项目（Tassone，PI）将是研究中心的唯一临床组成部分 格兰特，但在该项目的假设中有重要的分子成分。其他4个项目 具有主要的分子和/或神经生物学重点；但是，临床问题有些方面 参与他们的假设。 与招募患者有关的分子发现对于包含的假设至关重要 这些项目和分子测量将在统计分析中经常使用。已经显示 分子变异对物理参数有重大影响（Tassone，Hagerman等，1999; Loesch，Huggins等。 2004年），MRI体积发现（Mostofsky等，1998； Moore等，2002； Cohen等。 2006年），功能性MRI研究（Menon，Kwon等，2000），认知测量（Kaufmann，Abrams等，1999; Tassone，Hagerman等。 1999; Loesch，Huggins等。 2004年），情感功能和心理 发现（Hessl，Dyer-Friedman等，2001； Hessl，Tassone等，2005）。例如，在筛选项目中 我们假设分子变量将对医学/神经系统，认知， 语言，行为和社会参与。 核心将包含以下组件，每个组件在D节中详细描述： 1。招募患者 2。临床评估 3。分子剖面表征