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

描述（由申请人提供）：Klinefelter综合征（KS/XXY）是人类最常见的染色体异常（1:6 0男性），是研究遗传因素和生殖激素在神经发育中的相互作用的良好模型。患有KS的男性出现语言认知障碍、执行功能障碍、社会心理问题和运动技能缺陷的几率增加。大多数受影响的男性在青春期出现睾酮缺乏，但缺乏关于睾酮替代疗法对KS的心理和运动影响的客观数据。在这里，我们提出了第一个安慰剂对照研究，睾酮治疗对青少年KS的心理和运动影响。我们假设，在KS/XXY的青春期早期开始的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会影响对睾酮治疗的反应。在本研究项目中，我们的目标是：(1)研究睾丸激素治疗对青春期早期KS/XXY男性的心理和运动影响；(2)研究影响KS/XXY临床表型和对睾丸激素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，在青春期早期开始睾酮治疗可以改善注意力和个人适应的自我报告，并且不会导致负面行为的增加，并且雄激素受体基因CAG重复多态性短的个体对睾酮治疗的反应比CAG长多态性的个体更好。为了实现我们的目标，我们将在Tanner 2-3名KS/XXY男性患者中进行一项随机、前瞻性、双盲、安慰剂对照的睾酮替代疗法试验，在6个月和12个月的治疗后，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染色体的亲本起源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患者的睾酮治疗指南，并将提高对KS病理生理学的理解。作为发育-行为儿科学的一名亚专家，我致力于成为一名独立的研究者，研究项目重点是了解激素和遗传因素在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中的作用，并开展临床试验，开发循证治疗方法，以改善儿童的医疗和心理结果。本申请概述了五个主要的职业发展目标，这些目标将：(1)导致神经遗传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，以加强未来的研究努力，(4)增加对生殖激素对神经发育影响的当前神经影像学和动物研究的理解，(5)提高在神经发育和神经遗传疾病儿童弱势群体中应用当前生物伦理原则设计研究的能力。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。在神经心理学，行为遗传学，神经内分泌学和生物统计学方面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，并将利用儿童医院和加州大学丹佛分校科罗拉多临床与转化研究所的强大基础设施，为研究和职业发展提供支持。我有一个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-表现型研究、神经遗传综合征、发育障碍、生物伦理学和分子生物学方面有着广泛而成功的研究事业。我的机构承诺为研究提供保护时间，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，课程学费/费用，以及成功完成研究项目所需的任何额外支持，并加强我的职业发展成为一名独立研究者。

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.