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: 8190135
• 负责人: Nicole Renee Tartaglia
• 金额: $ 17.24万
• 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/8190135
• 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; Commit; Conduct Clinical Trials; Confounding Factors (Epidemiology); Congenital chromosomal disease; Consultations; DNA; Data; Databases; Development; Developmental Disabilities; Disease; Emotional disorder; Employment; Endocrinology; Evidence based treatment; 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; 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; skills; social; 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. PUBLIC HEALTH RELEVANCE: Klinefelter syndrome (47,XXY) affects over 230,000 males in the United States, and the hypogonadism (testosterone deficiency) associated with this syndrome leads to health problems and may also increase morbidity by negatively impacting psychological functioning, attention, behavior, and motor skills. This study will determine if there are psychological and/or motor benefits to earlier initiation of treatment in adolescents with XXY/Klinefelter syndrome, which would impact clinical care guidelines in this common genetic disorder. Understanding the genetic factors of the X chromosome related to the characteristics seen in males with XXY/Klinefelter syndrome is important to target neural pathways and to develop interventions.

描述（由申请方提供）：Klinefelter综合征（KS/XXY）是人类最常见的染色体异常（1：650男性），是研究遗传因素和生殖激素对神经发育相互作用的极好模型。KS男性患者的言语认知障碍、执行功能障碍、心理社会问题和运动技能缺陷的发生率增加。睾酮缺乏症的发展在青春期在大多数受影响的男性，但客观数据的心理和运动的影响，睾酮替代治疗KS是缺乏的。在这里，我们提出了有史以来第一次安慰剂对照研究的心理和运动的影响，睾酮治疗青少年与KS。我们假设，在青春期早期开始的KS/XXY睾酮治疗将导致执行功能，社会心理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）研究睾酮治疗对早期青春期KS/XXY男性患者的心理和运动影响;（2）研究影响KS/XXY患者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染色体的父母来源。我们的初步研究表明，在青春期早期开始的睾酮治疗改善了注意力和自我报告的个人调整，并没有导致增加的负面行为，并与雄激素受体基因的短CAG重复多态性的个人有一个改善睾酮治疗的反应相比，长CAG多态性。为了实现我们的目标，我们将在患有KS/XXY的坦纳2-3名男性中进行睾酮替代疗法的随机、前瞻性、双盲、安慰剂对照试验，在治疗6个月和12个月后，比较睾酮与安慰剂的心理因素（执行功能、注意力/抑制、语言流畅性）、行为（社会适应、攻击）和运动技能（力量、协调）。我们还将评估AR基因的多态性和额外X染色体的起源父母是否与临床表型或对睾酮治疗的反应相关。结果将影响KS/XXY患者的睾酮治疗指南，并将导致对KS病理生理学的更好理解。 作为发展行为儿科学的子专家，我致力于成为一名独立的研究人员，其研究项目专注于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，并进行临床试验，以开发循证治疗，改善儿童的医疗和心理结果。该申请概述了五个主要的职业发展目标，将（1）导致临床试验设计和执行神经遗传性疾病的专业化，（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）增加对当前神经成像和生殖激素对神经发育影响的动物研究的理解，以及（5）提高应用当前的生物伦理学原则设计在患有神经发育和神经遗传性疾病的儿童弱势群体中进行研究的能力。这些目标将通过在研究项目，指导会议，个性化的教程，并在相关的研究讨论组和研究会议的参与直接经验达到。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导致临床科学硕士学位。 该研究项目将通过一个名为eXtraordinarY Kids Clinic的独特诊所招募受试者，并将利用儿童医院和UC-Denver科罗拉多临床与转化研究所强大的基础设施进行研究和职业发展支持。我拥有一支强大的导师和合作者团队，他们在心理学，性染色体异常结果，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。我的机构已承诺提供受保护的研究时间，额外的研究支持，包括研究空间，研究药房服务，统计和数据库支持，生物伦理咨询，学费/课程费，以及成功完成研究项目所需的任何额外支持，并提高我的职业发展成为一名独立的研究者。 公共卫生相关性：Klinefelter综合征（47，XXY）影响了美国超过230，000名男性，与该综合征相关的性腺功能减退症（睾酮缺乏症）导致健康问题，并可能通过对心理功能，注意力，行为和运动技能产生负面影响而增加发病率。这项研究将确定XXY/Klinefelter综合征青少年早期开始治疗是否有心理和/或运动益处，这将影响这种常见遗传疾病的临床护理指南。了解与XXY/Klinefelter综合征男性患者特征相关的X染色体遗传因素对于靶向神经通路和制定干预措施非常重要。