Interrogating Fatty Acid Metabolism Impairment andClinical Correlates in Males with Klinefelter Syndrome

研究男性克兰费尔特综合征患者的脂肪酸代谢损伤及其临床相关性

基本信息

批准号：
10501374
负责人：
Shanlee Davis
金额：
$ 31.1万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10501374
关键词：
Adipose tissue Adolescent and Young Adult Adult Affect Age Agonist Androgens Aneuploidy Area Binding Biopsy Body mass index Cardiovascular Diseases Chronic Clinical Complex Data Defect Development Disease Dyslipidemias Energy Metabolism Exercise Failure Fasting Fatigue Fatty Acids Fatty acid glycerol esters Fenofibrate Fibrates Foundations Functional disorder Future Gene Expression Genes Genetic Diseases Genetic Materials Genetic Transcription Goals Health High Density Lipoprotein Cholesterol High Prevalence Hyperplasia Hypertriglyceridemia Hypogonadism Impairment Inborn Errors of Metabolism Indirect Calorimetry Individual Infertility Inflammation Insulin Resistance Intervention Intervention Studies Investigation Klinefelter&apos s Syndrome Life Ligands Lipids Measures Metabolic Metabolic Pathway Metabolism Mission Mitochondria Molecular Morbidity - disease rate Muscle Mitochondria National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Obesity Oral Outcome Oxidative Phosphorylation Oxidative Stress PPAR alpha Participant Pathology Pathway interactions Patient Self-Report Patient-Focused Outcomes Pharmaceutical Preparations Phenotype Physiology Plasma Protocols documentation Quality of life Regulator Genes Rest Role Secondary to Skeletal Muscle Testing Testosterone Therapeutic Intervention Tissue-Specific Gene Expression Tissues Up-Regulation Venous blood sampling Whole Blood Work X Chromosome Youth base cardiometabolism clinical phenotype cohort differential expression early childhood epidemiology study exercise intolerance experience fatty acid metabolism functional restoration improved improved outcome male men metabolic phenotype metabolome mortality negative affect novel oxidation sex chromosome aneuploidy targeted treatment theories transcription factor transcriptome transcriptome sequencing translational study uptake

项目摘要

ABSTRACT Klinefelter syndrome (KS) is a genetic condition affecting 1 in 600 males who have an additional X chromosome (47,XXY) associated with multisystem manifestations and increased mortality secondary to disorders of insulin resistance. One of the hallmark features of KS is primary testicular failure resulting in hypogonadism, and to date androgen treatment has been the only therapeutic intervention studied in these individuals. However, insulin resistance and abnormal metabolism have been observed in youth with KS prior to the onset of testicular hypogonadism. Furthermore, testosterone replacement does not ameliorate these cardiometabolic deficits that the majority of these individuals experience. The underlying molecular mechanisms for the high prevalence of insulin resistance and exercise intolerance observed in KS are unknown. This application proposes that the additional X chromosome leads to metabolic aberrations that can be targeted for therapeutic intervention. Peroxisome proliferator-activated receptor alpha (PPAR-α) is transcription factor that regulates the expression of genes controlling fatty acid metabolism, inflammation, and oxidative stress. Low PPAR-α activity is associated with cardiometabolic profiles similar to that observed in KS, including adiposity, dyslipidemia, and exercise intolerance. Our preliminary data have shown a metabolome and transcriptome consistent with insufficient activity of the PPAR-α complex in males with KS. The central hypothesis of this study is that lower PPAR-α activity contributes to the cardiometabolic phenotype in KS and that increasing PPAR-α activity via PPAR-α agonist treatment will result in upregulation of gene transcription that will improve cardiometabolic physiology. In this proof-of-concept trial, we will first compare expression of PPAR-α-regulated genes from whole blood and skeletal muscle in adolescent and young adult males with and without KS, as well as systemic fat oxidation during submaximal prolonged exercise and tissue-specific mitochondrial ß-oxidation. Resting energy expenditure, metabolite concentrations, and patient-centered outcomes will also be obtained and compared between groups. The KS cohort will then receive intervention with a PPAR- α agonist (fenofibrate) for one month, and all outcomes will be reassessed. This study will lay the foundation for future investigation of the first ever non-androgen treatment to improve insulin resistance and exercise intolerance in males with KS. The study aims support the mission and priority areas of the NIDDK and are expected to have direct clinical implications for individuals with KS.

抽象的克兰费尔特综合征 (KS) 是一种遗传性疾病，每 600 名男性中就有 1 名有额外的 X 基因染色体（47，XXY）与多系统表现和继发死亡率增加相关 KS 的标志性特征之一是导致原发性睾丸衰竭。性腺功能减退症，迄今为止，雄激素治疗是这些领域研究的唯一治疗干预措施然而，在患有 KS 的青少年中观察到胰岛素抵抗和代谢异常。此外，睾酮替代疗法并不能改善这些症状。大多数人都会经历心脏代谢缺陷。在 KS 中观察到的胰岛素抵抗和运动不耐受高发生率的机制是未知该申请提出额外的 X 染色体会导致代谢异常。过氧化物酶体增殖物激活受体α（PPAR-α）是治疗干预的目标。调节控制脂肪酸代谢、炎症和炎症的基因表达的转录因子低 PPAR-α 活性与心脏代谢特征相关，类似于 KS 中观察到的情况，包括肥胖、血脂异常和运动不耐受。我们的初步数据显示了代谢组。和转录组与 KS 男性 PPAR-α 复合物活性不足一致。这项研究的假设是，较低的 PPAR-α 活性有助于 KS 和通过 PPAR-α 激动剂治疗增加 PPAR-α 活性将导致基因转录上调这将改善心脏代谢生理学在这个概念验证试验中，我们将首先比较青少年和年轻成年男性全血和骨骼肌中 PPAR-α 调节的基因没有 KS，以及次最大长时间运动和组织特异性期间的全身脂肪氧化线粒体 β-氧化。静息能量消耗、代谢物浓度和以患者为中心的。还将获得结果并在各组之间进行比较，然后 KS 队列将接受干预。使用 PPAR-α 激动剂（非诺贝特）治疗一个月，所有结果将重新评估。为未来研究第一个改善胰岛素抵抗的非雄激素治疗奠定了基础该研究旨在支持 NIDDK 的使命和优先领域以及预计对 KS 患者具有直接的临床意义。