Effects of Testosterone and Genetic Factors on Psychological and Motor Function i

睾酮和遗传因素对心理和运动功能的影响 i

• 批准号: 8898244
• 负责人: Nicole Renee Tartaglia
• 金额: $ 17.84万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8898244
• 关键词: Adolescence; Adolescent; Adult; Affect; Age; Aggressive behavior; Androgen Receptor; Animal Experimentation; Attention; Behavior; Behavioral; Behavioral Genetics; Bioethics; Biometry; Blood specimen; CAG repeat; Case Series; Characteristics; Child; Chromosome abnormality; Clinic; Clinical Research; Clinical Sciences; Clinical Trials; Clinical Trials Design; Cognitive; Cognitive deficits; Colorado; Conduct Clinical Trials; Confounding Factors (Epidemiology); Congenital chromosomal disease; Consultations; DNA; Data; Databases; Development; Developmental Disabilities; Disease; Emotional disorder; Employment; Endocrinology; Evidence based treatment; Executive Dysfunction; Factor X; Fees; Functional disorder; Genetic; Genetic Polymorphism; Genotype; Guidelines; Gynecomastia; Health; Hereditary Disease; Hormonal; Human; Hypogonadism; Impaired cognition; Impairment; Individual; Inherited; Institution; Intervention; Klinefelter' s Syndrome; Lead; Length; Male Adolescents; Master' s Degree; Medical; Mentors; Modeling; Molecular Biology; Molecular Diagnostic Techniques; Moods; Morbidity - disease rate; Motor; Motor Skills; Neural Pathways; Neuroendocrinology; Neuropsychology; Outcome; Parents; Patient Self-Report; Patients; Pediatric Hospitals; Pediatrics; Pharmaceutical Services; Phenotype; Placebos; Psychological Factors; Psychological Impact; Psychology; Puberty; Randomized; Receptor Gene; Recruitment Activity; Research; Research Design; Research Infrastructure; Research Institute; Research Personnel; Research Project Grants; Research Support; Role; Sampling; Severities; Social Adjustment; Social Functioning; Staging; Syndrome; Testosterone; Time; Time Factors; Translational Research; United States; Vulnerable Populations; X Chromosome; career; career development; clinical care; clinical phenotype; clinical practice; cognitive skill; double-blind placebo controlled trial; early adolescence; executive function; experience; externalizing behavior; improved; male; neurodevelopment; neurogenetics; neuroimaging; placebo controlled study; programs; prospective; psychologic; psychological outcomes; psychosocial; reproductive hormone; research and development; response; sex; social; social attention; social skills; symposium; testosterone replacement therapy

DESCRIPTION (provided by applicant): Klinefelter syndrome (KS/XXY) is the most common chromosomal abnormality in humans (1:650 males) and represents an excellent model in which to study the interplay between genetic factors and reproductive hormones on neurodevelopment. Males with KS have increased rates of verbal cognitive impairments, executive dysfunction, psychosocial problems, and motor skills deficits. Testosterone deficiency develops during adolescence in the majority of affected males, but objective data about the psychological and motor effects of testosterone replacement therapy in KS is lacking. Here we propose the first-ever placebo- controlled study of the psychological and motor effects of testosterone therapy in adolescents with KS. We hypothesize that testosterone therapy initiated in early puberty in KS/XXY will lead to improvements in executive function, psychosocial functioning, and motor skills, while externalizing behaviors will remain unchanged. We also hypothesize that genetic polymorphisms in the androgen receptor gene influence response to testosterone therapy. In the proposed research project we aim to: (1) study the psychological and motor effects of testosterone therapy in early adolescent males with KS/XXY and (2) investigate genetic factors influencing the clinical phenotype and response to testosterone therapy in KS/XXY, including androgen-receptor (AR) polymorphisms and parent-of-origin of the extra X chromosome. Our preliminary studies suggest that testosterone therapy started in early adolescence improves attention and self-report of personal adjustment, and does not lead to increased negative behaviors, and that individuals with the short CAG-repeat polymorphism of the androgen receptor gene have an improved response to testosterone therapy compared to the long CAG polymorphism. To accomplish our aims, we will conduct a randomized, prospective, double- blind, placebo-controlled trial of testosterone replacement therapy in Tanner 2-3 males with KS/XXY, comparing psychological factors (executive function, attention/inhibition, verbal fluency), behavior (social adjustment, aggression) and motor skills (strength, coordination) in testosterone versus placebo after 6 and 12 months of therapy. We will also evaluate if polymorphisms in the AR gene and the parent-of-origin of the extra X chromosome are related to the clinical phenotype or response to testosterone treatment. Results will influence treatment guidelines for testosterone in patients with KS/XXY and will lead to improved understanding of the pathophysiology of KS. As a subspecialist in Developmental-Behavioral Pediatrics, I am committed to becoming an independent investigator with a research program focused on understanding the role of hormonal and genetic factors on neurodevelopment and behavior in children with sex chromosomal disorders and other neurogenetic syndromes, and in conducting clinical trials to develop evidence-based treatments to improve medical and psychological outcomes of children. This application outlines five primary career development aims that will (1) lead to specialization in clinical trials design and execution for neurogenetic disorders, (2,3) enhance experience in neuropsychology and molecular diagnostic methods to enhance future research endeavors, (4) increase understanding of current neuroimaging and animal research on reproductive hormone effects on neurodevelopment, and (5) enhance abilities to design research in vulnerable populations of children with neurodevelopmental and neurogenetic disorders applying current bioethical principles. These aims will be reached through direct experience during the research project, mentoring sessions, personalized tutorials, and participation in related research discussion groups and research conferences. Supplementary didactic coursework in neuropsychology, behavioral genetics, neuroendocrinology, and biostatistics will also lead to a Masters degree in Clinical Science. This research project will recruit subjects through a unique clinic called the eXtraordinarY Kids Clinic, and will take advantage of strong infrastructure for research and career development support at The Children's Hospital and the UC-Denver Colorado Clinical & Translational Research Institute. I have a assembled a strong team of mentors and collaborators with broad and successful research careers in psychology, outcomes in sex chromosomal abnormalities, endocrinology, clinical trials, genotype-phenotype studies, neurogenetic syndromes, developmental disabilities, bioethics, and molecular biology. My institution has committed to providing protected time for research, additional research supports including research space, research pharmacy services, statistical and database support, bioethical consultation, tuition/fees for coursework, and any additional supports needed to successfully complete the research project and to enhance my career development into an independent investigator.

描述（由申请人提供）：克兰费尔特综合征 (KS/XXY) 是人类（1:650 男性）中最常见的染色体异常，是研究遗传因素和生殖激素之间对神经发育的相互作用的绝佳模型。患有 KS 的男性言语认知障碍、执行功能障碍、心理社会问题和运动技能缺陷的发生率更高。大多数受影响的男性在青春期出现睾酮缺乏症，但缺乏关于睾酮替代疗法对 KS 心理和运动影响的客观数据。在这里，我们提出了有史以来第一项关于睾酮治疗对 KS 青少年心理和运动影响的安慰剂对照研究。我们假设在 KS/XXY 青春期早期开始的睾酮治疗将导致执行功能、心理社会功能和运动技能的改善，而外化行为将保持不变。我们还假设雄激素受体基因的遗传多态性影响对睾酮治疗的反应。 在拟议的研究项目中，我们的目标是：(1) 研究睾酮治疗对患有 KS/XXY 的早期青春期男性的心理和运动影响；(2) 研究影响 KS/XXY 临床表型和睾酮治疗反应的遗传因素，包括雄激素受体 (AR) 多态性和额外 X 染色体的亲本来源。我们的初步研究表明，在青春期早期开始的睾酮治疗可以提高注意力和个人适应的自我报告，并且不会导致消极行为的增加，并且具有雄激素受体基因短 CAG 重复多态性的个体对个人适应的反应有所改善。睾酮疗法与长CAG多态性相比。为了实现我们的目标，我们将对 2-3 名患有 KS/XXY 的 Tanner 男性进行睾酮替代疗法的随机、前瞻性、双盲、安慰剂对照试验，比较心理因素（执行功能、注意力/抑制、言语流畅性）治疗 6 个月和 12 个月后，睾酮组与安慰剂组的行为（社会适应、攻击性）和运动技能（力量、协调性）的比较。我们还将评估 AR 基因和额外 X 染色体的亲本来源的多态性是否与临床表型或对睾酮治疗的反应有关。结果将影响 KS/XXY 患者睾酮治疗指南，并将提高对 KS 病理生理学的了解。 作为发育行为儿科的专科医生，我致力于成为一名独立研究者，其研究项目重点是了解激素和遗传因素对性染色体疾病和其他神经遗传综合征儿童神经发育和行为的作用，并进行临床研究开发循证治疗方法以改善儿童的医疗和心理结果的试验。该申请概述了五个主要职业发展目标，这些目标将（1）导致神经遗传性疾病临床试验设计和执行的专业化，（2,3）增强神经心理学和分子诊断方法的经验，以加强未来的研究工作，（4）增加理解（5）提高应用当前生物伦理学原理对患有神经发育和神经遗传疾病的儿童弱势群体进行研究的能力。这些目标将通过研究项目期间的直接经验、指导会议、个性化教程以及参与相关研究讨论小组和研究会议来实现。神经心理学、行为遗传学、神经内分泌学和生物统计学的补充教学课程也将获得临床科学硕士学位。 该研究项目将通过一家名为 eXtraordinarY Kids Clinic 的独特诊所招募受试者，并将利用儿童医院和加州大学丹佛分校科罗拉多州临床与转化研究所强大的研究和职业发展支持基础设施。我组建了一支强大的导师和合作者团队，他们在心理学、性染色体异常、内分泌学、临床试验、基因型-表型研究、神经遗传综合征、发育障碍、生物伦理学和分子生物学方面拥有广泛而成功的研究生涯。我的机构致力于提供受保护的研究时间、额外的研究支持，包括研究空间、研究药学服务、统计和数据库支持、生物伦理咨询、课程学费/费用，以及成功完成研究项目和加强研究所需的任何额外支持。我的职业发展成为一名独立调查员。

项目成果

A review of trisomy X (47,XXX).

X 三体 (47,XXX) 的回顾。

• 发表时间: 2010-05-11
• 作者: Tartaglia, Nicole R;Howell, Susan;Sutherland, Ashley;Wilson, Rebecca;Wilson, Lennie
• 通讯作者: Wilson, Lennie

Klinefelter syndrome (KS). Foreword.

克兰费尔特综合征（KS）。

• 发表时间: 2010-12
• 作者: Rogol, Alan D;Tartaglia, Nicole
• 通讯作者: Tartaglia, Nicole

Cognitive and medical features of chromosomal aneuploidy.

染色体非整倍体的认知和医学特征。

• 发表时间: 2013
• 作者: Hutaff;Cordeiro, Lisa;Tartaglia, Nicole
• 通讯作者: Tartaglia, Nicole

The eXtraordinarY Kids Clinic: an interdisciplinary model of care for children and adolescents with sex chromosome aneuploidy.

非凡儿童诊所：针对性染色体非整倍体儿童和青少年的跨学科护理模式。

• 发表时间: 2015
• 作者: Tartaglia, Nicole;Howell, Susan;Wilson, Rebecca;Janusz, Jennifer;Boada, Richard;Martin, Sydney;Frazier, Jacqueline B;Pfeiffer, Michelle;Regan, Karen;McSwegin, Sarah;Zeitler, Philip
• 通讯作者: Zeitler, Philip

Expanding the phenotype of Triple X syndrome: A comparison of prenatal versus postnatal diagnosis.

扩大三 X 综合征的表型：产前与产后诊断的比较。

• 发表时间: 2016
• 作者: Wigby, Kristen;D'Epagnier, Cheryl;Howell, Susan;Reicks, Amy;Wilson, Rebecca;Cordeiro, Lisa;Tartaglia, Nicole
• 通讯作者: Tartaglia, Nicole