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: 8309989
• 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/8309989
• 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.

描述（由申请人提供）：KlineFelter综合征（KS/XXY）是人类中最常见的染色体异常（1：650雄性），它代表了一个出色的模型，在该模型中，研究遗传因素与神经产物中生殖激素之间的相互作用。患有KS的男性具有口头认知障碍，执行功能障碍，社会心理问题和运动技能缺陷的率提高。在大多数受影响的男性中，睾丸激素缺乏症会在青春期发展，但缺乏有关KS中睾丸激素替代疗法的心理和运动影响的客观数据。在这里，我们提出了有关KS青少年睾丸激素治疗的心理和运动影响的首次安慰剂对照研究。我们假设在KS/XXY的早期青春期开始的睾丸激素疗法将改善执行功能，社会心理功能和运动技能，而外部化行为将保持不变。我们还假设雄激素受体基因中的遗传多态性影响对睾丸激素治疗的反应。 在拟议的研究项目中，我们的目的是：（1）研究睾丸激素治疗的心理和运动作用在早期的KS/XXY青春期男性中，（2）研究影响临床表型和对KS/XXY睾丸激素治疗的反应的遗传因素，包括雄激素 - 受体（AR）多形多态性和X型XX的遗传因素。我们的初步研究表明，睾丸激素治疗在青春期早期开始，可以提高个人调整的注意力和自我报告，并不会导致负面行为增加，并且与长CAG多态性相比，雄激素受体基因的短CAG重复多态性多态性的个人对睾丸激素治疗的反应不佳。为了实现我们的目标，我们将进行一项随机，前瞻性，双盲，安慰剂对照试验的睾丸激素替代疗法试验，对Tanner 2-3名男性使用KS/XXY进行比较，比较心理因素（执行功能，注意力/抑制，口头抑制，言语，行为，社交调整，攻击，攻击）和运动能力（社会技能），在疗程中，疗法疗法和疗法疗法均可进行疗程，术中的疗法均可进行疗程，均为疗程均可进行疗程。我们还将评估AR基因中的多态性和额外X染色体的父母 - 原始蛋白与临床表型或对睾丸激素治疗的反应有关。结果将影响KS/XXY患者睾丸激素的治疗​​指南，并会提高对KS病理生理学的了解。 作为发育行为的专业人士，我致力于成为一名独立研究者，其研究计划的重点是理解激素和遗传因素对性染色体疾病儿童的神经发育和行为的作用，以及在循证临床试验中，以改善医学疗法的性临床试验，以改善医学和心理学。该应用程序概述了五个主要的职业发展目标，该目标将（1）在临床试验设计和神经遗传疾病的执行方面进行专业化，（2,3）增强神经心理学和分子诊断方法的经验，以增强未来的研究努力，（4）对当前神经模仿和动物对NEURODINER对NEURODINES对NEURODENTION的研究的了解，并在NEURODENTING上提高了对NEURODINES的研究，并在5个研究中对5种效应（5），以及（5）（5）（5）（5）（5）（5使用当前生物伦理学原理的神经发育和神经遗传疾病的儿童的种群。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。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“非凡儿童诊所”的独特诊所招募受试者，并将利用强大的基础设施在儿童医院和UC-Denver Colorado临床和转化研究所的研究和职业发展支持。我组建了一支强大的导师和合作者团队，具有广泛而成功的心理学研究职业，性别染色体异常的成果，内分泌学，临床试验，基因型 - 表型研究，神经遗传综合症，发育障碍，生物伦理学，生物伦理学和分子生物学。我的机构已致力于提供受保护的研究时间，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，课程学费，以及成功完成研究项目所需的任何其他支持，并将我的职业发展提高我的职业发展为独立研究者所需的任何其他支持。