Disorders of Sex Development: Platform for Basic and Translational Research

性发育障碍：基础和转化研究平台

基本信息

批准号：
8646162
负责人：
DAVID Eric. SANDBERG
金额：
$ 7.84万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-26 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8646162
关键词：
Accounting Advocate Affect Algorithms Anatomy Appearance Basic Science Biochemical Biological Biology Birth Candidate Disease Gene Child Clinical Clinical Management Clinical Research Clitoris Consensus Cryptorchidism DNA Data Decision Making Development Diagnosis Diagnostic Effectiveness Emotional Ensure Environment Equilibrium Europe European Union Evaluation Family Female Fertility Financial Support Fostering Foundations Functional disorder Future Gender Genetic Genital system Genotype Goals Guidelines Health Health Personnel Health Professional Healthcare Healthcare Systems Human Hypertrophy Hypospadias Incidence Information Technology Interdisciplinary Study Investigation Knowledge Leadership Learning Left Link Longevity Longitudinal Studies Measures Medical Medical Care Team Medical Genetics Minor Molecular Diagnosis North America Operative Surgical Procedures Outcome Parents Pathology Pathway interactions Patient Care Patients Persons Phenotype Physiological Population Positioning Attribute Procedures Process Protocols documentation Proxy Quality of life Quality-of-Life Assessment Recommendation Records Registries Reporting Research Research Design Research Infrastructure Research Personnel Resources Sampling Scientist Sequence Analysis Sexual Development Sexual Dysfunction Site Standardization Time Translational Research Translations Treatment Protocols Uncertainty Uterus Variant base behavioral health cancer risk clinical care clinical practice design evidence base experience health care delivery health related quality of life improved indexing insight male malformation multidisciplinary novel patient registry prospective psychologic psychosocial research and development sex sex development disorder skills social success tool

项目摘要

Disorders of sex development (DSD) are phenotypically heterogeneous, ranging from minor genital malformations (hypospadias, cryptorchidism, hypertrophy of the clitoris) to genital ambiguity. In the aggregate, DSD have an estimated incidence of about 1%. DSD can result in severe consequences for behavioral health, fertility, cancer risk and quality of life. For families, the birth of a child with a DSD, and the accompanying uncertainty about future psychological and sexual development, is believed to be extraordinarily stressful. Recently, the debate over clinical management of DSD, in particular gender assignment and genital surgery, has intensified; yet the scientific data on patient outcomes have remained very incomplete. Major obstacles to optimal clinical management of DSD include gaps in understanding of pathophysiology, impeding precise diagnostic categorization, along with the absence of prospective longitudinal studies of health and quality of life outcomes. This proposal delivers a platform for hypothesis-based research on the mechanisms of sex development and evidence-based care for patients and families affected by DSD. Aim 1 identifies novel genetic mechanisms of sex development and improves understanding of the pathophysiology and molecular diagnosis of DSD by a step-wise approach of specific DNA capture and sequencing, analysis of copy number variants, and identification of novel candidate genes for DSD. Aim 2 delivers standardized tools for reliable phenotypic descriptions across multiple study sites and investigators, including radiological, biochemical, histological evaluations and descriptions of genital phenotype and post- surgical appearance and function, facilitating interpretation of genetic, gender, and quality of life outcomes Aim 3 identifies short and medium-term outcomes by delivering a comprehensive psychosocial and health-related quality of life assessment battery using psychometrically robust measures suitable for use in routine clinical care, a necessary step leading to evidence-based psychosocial treatment protocols. Aim 4 builds a sustainable research infrastructure and ensures rapid translation of new evidence into ongoing clinical practice by integrating standardized DSD diagnostic and treatment protocols and fostering the transfer of best practices in healthcare delivery across network sites. This registry provides the analytic platform by which data are collected, analyzed, and shared among researchers and sites, while a collaborative network will supply the foundation for multidisciplinary basic, clinical, and translational research. This unique combination of genetic, phenotypic and psychosocial approaches will transform participating sites into self-sustaining DSD "centers of excellence" for clinical care along with the added value of a registry serving as a critical resource for hypothesis-driven research.

性发育障碍 (DSD) 具有多种表型异质性，从轻微的生殖器畸形（尿道下裂、隐睾、阴蒂肥大）到生殖器模糊。总体而言，DSD 的发病率估计约为 1%。 DSD 可能会对行为健康、生育能力、癌症风险和生活质量造成严重后果。对于家庭来说，患有 DSD 的孩子的出生以及随之而来的未来心理和性发育的不确定性被认为是异常紧张的。最近，关于 DSD 临床管理的争论，特别是性别分配和生殖器手术，已经加剧。然而，关于患者结果的科学数据仍然非常不完整。 DSD 最佳临床管理的主要障碍包括对病理生理学的理解存在差距，妨碍精确的诊断分类，以及缺乏对健康和生活质量结果的前瞻性纵向研究。该提案为基于假设的性发育机制研究以及为受 DSD 影响的患者和家庭提供循证护理提供了一个平台。目标 1 通过特定 DNA 捕获和测序、拷贝数变异分析以及 DSD 新候选基因鉴定的逐步方法，确定性发育的新遗传机制，并提高对 DSD 病理生理学和分子诊断的理解。目标 2 提供标准化工具，用于跨多个研究地点和研究人员进行可靠的表型描述，包括放射学、生化、组织学评估以及生殖器表型和术后外观和功能的描述，促进对遗传、性别和生活质量结果的解释目标 3通过使用适用于常规临床护理的心理测量稳健措施，提供全面的心理社会和健康相关的生活质量评估电池，确定短期和中期结果，这是实现基于证据的心理社会的必要步骤治疗方案。目标 4 建立可持续的研究基础设施，并通过整合标准化 DSD 诊断和治疗方案并促进跨网络站点的医疗保健提供最佳实践的转移，确保将新证据快速转化为持续的临床实践。该注册中心提供了一个分析平台，通过该平台可以在研究人员和研究中心之间收集、分析和共享数据，而协作网络将为多学科基础、临床和转化研究提供基础。这种遗传、表型和心理社会方法的独特组合将把参与地点转变为自我维持的 DSD 临床护理“卓越中心”，同时登记册作为假设驱动研究的关键资源，具有附加值。