The effects of Mkrn3 on delayed puberty

Mkrn3 对青春期延迟的影响

• 批准号: 10409545
• 负责人: Stephanie Anne Roberts
• 金额: $ 16.79万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10409545
• 关键词: Accounting; Area; Bilateral; Bone Density; Brain; Caenorhabditis elegans; Characteristics; Child; Child Health; Chromosomes; Clinical; Code; Complex; DNA Sequence Alteration; Data; Delayed Puberty; Developmental Process; Diagnosis; Disease; Disease Management; Dynorphins; Estrus; Female; Future; GNRH1 gene; Genes; Genetic; Goals; Health; Human; Hypothalamic structure; Impairment; Injections; Investigation; K-Series Research Career Programs; KISS1 gene; Klinefelter' s Syndrome; Lead; Life; Mediator of activation protein; Messenger RNA; Modeling; Mus; Neurokinin B; Neurons; Neuropeptides; Neurosecretory Systems; Patients; Periodicity; Phenotype; Physiological; Precocious Puberty; Premature Menopause; Proteins; Puberty; RNA Binding; Recombinant adeno-associated virus (rAAV); Regulation; Reporting; Reproduction; Ring Finger Domain; Risk; Role; Sex Differentiation; Structure; Structure of nucleus infundibularis hypothalami; Time; Transgenes; Transgenic Mice; Transgenic Organisms; Untranslated RNA; Variant; cohort; genetic variant; hypothalamic pituitary gonadal axis; improved; in vivo; inhibitor; innovation; long-term sequelae; loss of function mutation; mRNA Transcript Degradation; mouse model; neonatal mice; novel; overexpression; peer; premature; prepuberty; protein degradation; protein structure; psychosocial wellbeing; recombinant virus; reproductive; sex; therapeutic target; tool; ubiquitin-protein ligase

PROJECT SUMMARY Puberty is a remarkable time during which the body develops secondary sexual characteristics and becomes capable of reproduction. Puberty onset is due to a complex interplay of factors, including genetic influences. Genetic mutations in disorders of puberty, including central precocious puberty (CPP) and delayed puberty, provide windows into understanding the neuroendocrine mechanisms of puberty and reproduction. The most common genetic cause of precocious puberty is due to loss-of-function mutations in Makorin Ring Finger Protein 3 (MKRN3), and accounts for ~40% of familial CPP. The function and regulation of MKRN3 are not well understood, but its protein structure suggests E3 ubiquitin ligase and RNA binding activities. Expression of Mkrn3 is high in the mouse hypothalamus and rapidly declines before puberty onset. This supports its role as the first identified inhibitor of puberty onset, hypothesized to act upstream of GnRH and/or its activators, such as kisspeptin. The current proposal aims to explore if alterations in Mkrn3 expression can similarly lead to delayed pubertal onset using innovative mouse models and human investigation. Preliminary studies demonstrate a delayed puberty phenotype in wild type female mice injected intracerebroventricularly with a recombinant virus overexpressing Mkrn3. This current model will be used to explore MKRN3’s mechanism of action, including its impact on known neuroendocrine players in reproduction. This recombinant virus will be used to assess if Mkrn3 overexpression can also lead to hypogonadotropic hypogonadism postpubertally following bilateral stereotaxic injection into the arcuate nuclei of the hypothalamus. In a more specific model of overexpression, Mkrn3 will be selectively overexpressed in kisspeptin neurons using a novel transgenic mouse model to better identify MKRN3’s targets. Additionally, given the observation in preliminary studies that increases in Mkrn3 expression can delay puberty onset, a well-characterized cohort of children with delayed puberty will be screened for coding and non-coding variants in MKRN3 as this has not been previously explored. Delayed puberty puts children at risk for long-term health risks. Therefore, elucidating the impact and mechanisms of action of MKRN3 in delaying pubertal onset has important implications for advancing child health, including improving diagnosis and management of pubertal disorders and can serve as a future therapeutic target. Using the proposed tools to identify MKRN3’s targets of action is critical to understanding this key player in the neuroendocrine control of puberty and reproduction.

项目摘要 青春期是一个显着的时期，在此期间，身体发展第二性征， 能够繁殖。青春期的开始是由于复杂的相互作用的因素，包括遗传的影响。 青春期疾病的基因突变，包括中枢性性早熟（CPP）和青春期延迟， 提供了解青春期和生殖的神经内分泌机制的窗口。 性早熟最常见的遗传原因是由于Makorin环的功能丧失突变 指蛋白3（MKRN 3），占家族性CPP的约40%。MKRN 3的功能和调节是 其蛋白质结构提示E3泛素连接酶和RNA结合活性。表达 Mkrn 3的表达在小鼠下丘脑中很高，并在青春期开始前迅速下降。这支持了它的作用， 第一个确定的青春期发作抑制剂，假设作用于GnRH和/或其激活剂的上游，如 接吻素 目前的提议旨在探索Mkrn 3表达的改变是否同样会导致青春期延迟。 使用创新的小鼠模型和人类研究。初步研究表明， 脑室内注射重组病毒的野生型雌性小鼠的青春期表型 过表达Mkrn 3。目前的模型将用于探索MKRN 3的作用机制，包括其在细胞内的作用。 对生殖中已知神经内分泌参与者的影响。该重组病毒将用于评估Mkrn 3 过表达也可导致双侧立体定位后的低促性腺激素性性腺功能减退症 注射到下丘脑的弓状核。在更具体的过表达模型中，Mkrn 3将被 使用新型转基因小鼠模型在kisspeptin神经元中选择性过表达， MKRN 3的目标此外，考虑到在初步研究中观察到Mkrn 3表达增加， 可以延迟青春期的开始，将筛选一组特征良好的青春期延迟儿童进行编码 和MKRN 3中的非编码变体，因为这在以前没有被探索过。 青春期延迟会使儿童面临长期健康风险。因此，阐明影响和 MKRN 3延迟青春期开始的作用机制对促进儿童健康具有重要意义， 包括改善青春期疾病的诊断和管理， 目标使用所提出的工具来确定MKRN 3的行动目标对于理解这一关键角色至关重要 在青春期和生殖的神经内分泌控制中的作用。