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Post-transcriptional Pathways that Signal Leptin Regulation of Gonadotropes

瘦素对促性腺激素调节的转录后信号通路

基本信息

批准号：
9902541
负责人：
GWEN V CHILDS
金额：
$ 45.72万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902541
关键词：
Ablation Address Binding Clinical Protocols Clomiphene Data Development Diestrus Enterobacteria phage P1 Cre recombinase Equilibrium Exons Fasting Female Fertility Food deprivation (experimental)Frequencies Genetic Genetic Transcription Genetic Translation Goals Gonadal structure Gonadotropin Hormone Releasing Hormone Gonadotropin-Releasing Hormone Receptor Gonadotropins Human In Vitro Infertility Knowledge Lead Leptin Leptin deficiency Link Lipodystrophy Luteinizing Hormone Mediating Membrane Menarche Messenger RNA Metabolic Metabolism MicroRNAs Mission Modeling Molecular Mus Mutant Strains Mice Neurons Nutritional Nutritional status Ovulation Patients Periodicity Physiologic pulse Pituitary Gland Portal System Prevention Process Protein Isoforms Proteins Public Health RNA-Binding Proteins Receptor Gene Regulation Reporter Repression Reproduction Reproductive Process Research Resources Role Serum Signal Pathway Signal Transduction Site Testing Time Translations United States National Institutes of Health Untranslated RNA Up-Regulation genetic regulatory protein hypothalamic pituitary gonadal axis improved in vivo infertility treatment innovation knock-down knockout gene leptin receptor mouse model mutant novel novel diagnostics novel therapeutic intervention prevent receptor receptor expression reproductive success response restoration success

项目摘要

PROJECT SUMMARY/ABSTRACT The expression of GnRHRs is a critical, rate-limiting step in the reproductive process, however little is known about the mechanism behind the regulation of translation of GnRHR proteins. Gonadotrope functions may be limited in times of food deprivation, which is signaled by leptin deficiency, however there is a fundamental gap in understanding how leptin regulates gonadotropes. Leptin's importance to gonadotropes is highlighted by the infertile mouse model in which all isoforms of leptin receptors (LEPR) on gonadotropes are ablated, and the fact that the mutant gonadotropes have severely reduced GnRHR protein, but not mRNA levels. These findings provide important clues as to how leptin links fertility to metabolic status, however the molecular mechanisms underlying leptin control of gonadotropes are unknown. Our long-term goal is to fill this knowledge gap by identifying underlying mechanisms behind the infertility in the gonadotrope Lepr-null mutant mice. The central hypothesis to be tested is that loss of leptin signaling in gonadotropes prevents the normal diestrous upregulation of GnRH receptors causing a blunted or absent LH surge and infertility. A secondary hypothesis that leptin acts through posttranscriptional mechanisms to optimize gonadotrope function. The proposed studies will focus on three specific aims. Specific Aim 1 will determine if loss of leptin signaling in gonadotropes reduces fertility through prevention of the diestrous upregulation of GnRHR protein levels. These studies will ascertain if the Lepr-null gonadotropes are held in persistent diestrus because of low GnRHR proteins and if the normal surge in serum gonadotropins is absent. The efficacy of exogenous GnRH in the rescue of GnRHR levels in mutants and restoration of cyclicity and fertility will be tested. Specific Aim 2 studies will determine if leptin signaling to mRNA translational control mechanisms is required for gonadotrope function. These studies will globally assess leptin regulation of gonadotrope mRNA translation and specifically address control of Gnrhr mRNA translation. Genetic knockdown of identified candidate translational repressors will be used to restore GnRHR expression in mutant gonadotropes. Specific Aim 3 studies will determine if food deprivation recapitulates the effect of loss of leptin signaling to gonadotropes, including repression of Gnrhr mRNA translation. These in vivo studies will test the hypothesis that loss of leptin signaling during food deprivation also prevents diestrous upregulation of GnRHR. The studies will also determine if the in vitro deletion of identified translational control mechanisms (e.g. MSI, miRNAs) alleviates the fasting-induced repression of Gnrhr mRNA translation. Our research is innovative because it investigates the novel concept that leptin may regulate gonadotrope function at post-transcriptional levels. These findings are significant because clinical protocols used in infertility treatments (e.g. clomiphene) depend on normal responses to endogenous GnRH, which we have shown depends on normal leptin signaling.

项目总结/摘要 GnRHRs的表达是生殖过程中的一个关键的限速步骤，但很少有表达。了解GnRHR蛋白翻译调控背后的机制。促性腺功能可能在食物匮乏的时候受到限制，这是瘦素缺乏的信号，然而，了解瘦素如何调节促性腺激素的根本差距。瘦素对促性腺激素的重要性在于不育小鼠模型突出显示，在该模型中，促性腺激素上的瘦素受体（LEPR）的所有同种型都是事实上，突变的促性腺激素细胞严重减少了GnRHR蛋白，但不是mRNA 程度.这些发现为瘦素如何将生育能力与代谢状态联系起来提供了重要线索，瘦素控制促性腺激素的分子机制尚不清楚。我们的长期目标是通过确定促性腺激素Lepr无效不孕症背后的潜在机制，突变小鼠待检验的中心假设是，促性腺激素细胞中瘦素信号的丢失防止GnRH受体的正常非动情期上调，导致LH钝化或缺失激增和不育。瘦素通过转录后作用的次要假说优化促性腺激素功能的机制。拟议的研究将侧重于三个具体目标。特异性目标1将确定促性腺激素中瘦素信号传导的丧失是否通过预防促性腺激素释放激素受体蛋白水平的非动情期上调。这些研究将确定是否麻风零促性腺激素细胞由于低GnRHR蛋白而处于持续性间情期，并且如果血清中的正常激增没有促性腺激素。外源性GnRH在突变体和非突变体中GnRH受体水平拯救中的功效将测试周期性和生育力的恢复。具体目标2研究将确定瘦素信号是否 mRNA翻译控制机制是促性腺激素功能所必需的。这些研究将在全球范围内评估瘦素对促性腺激素mRNA翻译的调节，特别是对Gnrhr mRNA的控制翻译.已识别候选翻译阻遏物的基因敲低将用于恢复GnRHR 在突变型促性腺激素中的表达。具体目标3研究将确定食物剥夺是否重演了瘦素信号传导丢失对促性腺激素的影响，包括Gnrhr mRNA翻译的抑制。这些在体内研究将检验这一假设，即在食物剥夺期间，瘦素信号传导的丧失也阻止了间情。 GnRHR的上调。这些研究还将确定是否在体外缺失鉴定的翻译控制机制（如MSI，miRNA）阐明了空腹诱导的Gnrhr mRNA翻译抑制。我们的研究是创新的，因为它探讨了新的概念，瘦素可能调节促性腺激素在转录后水平发挥作用。这些发现是重要的，因为临床上使用的方案，不孕症的治疗（如克罗米酚）依赖于对内源性GnRH的正常反应，我们有所示取决于正常的瘦素信号传导。