Ovarian derived exosomal miRNA as a juvenile protective factors

卵巢来源的外泌体 miRNA 作为青少年保护因子

• 批准号: 10674254
• 负责人: MICHAL Mateusz MASTERNAK
• 金额: $ 28.66万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10674254
• 关键词: Adolescent; Aging; Animals; Blood; Blood Circulation; Cell Compartmentation; Cells; Data; Development; Diabetes Mellitus; Disease; Distant; Dwarfism; Elderly; Estradiol; Female; Genes; Genetic; Genome Stability; Goals; Gonadal Steroid Hormones; Gonadal structure; Health; Health Benefit; Hormonal; Hormones; Human; Hypersensitivity; Incidence; Inflammation; Insulin; Insulin Resistance; Life; Life Style; Link; Longevity; Membrane Lipids; Menopause; Metabolic syndrome; MicroRNAs; Molecular; Molecular Profiling; Mus; Organ; Ovarian; Ovarian Tissue; Ovarian aging; Ovary; PIK3CG gene; Pattern; Periodicity; Persons; Play; Population; Premenopause; Process; Production; Proto-Oncogene Proteins c-akt; Race; Regulation; Research; Role; Serum; Signal Pathway; Somatic Cell; Source; Steroids; Testing; Therapeutic; Tissues; Transplant Recipients; Transplantation; Vesicle; Weight Gain; age related; anti aging; base; circulating microRNA; dietary; differential expression; disorder risk; exosome; fetal; healthspan; improved; in vivo; inhibitor; insulin regulation; insulin sensitivity; insulin signaling; male; novel; ovarian reserve; ovary transplantation; prepuberty; preservation; protective factors; reproductive; reproductive function; reproductive longevity; reproductive organ; restoration; transcriptome

The long-term goal of our research is to identify the role of young ovaries in production of therapeutic juvenile protective factors in form of exosomes carrying putative pro-longevity microRNAs (miRNAs). With the growing population of elderly people, there is a growing incidence of age-related diseases including metabolic syndrome, insulin resistance and diabetes mellitus. There is a well-established link between health and the function of reproductive organs and longevity. Importantly, it was shown that transplanting young ovaries into old mice delays aging and increases lifespan by over 40%. Unfortunately, the detailed mechanism by which young ovaries provide these longevity benefits is still undetermined. One of the possible benefits could be linked to an enhanced production of sex hormones, yet it was also shown that eliminating sex hormone producing cells in ovaries before transplantation, still produced pro-longevity benefits. Importantly, for the purpose of this proposal our novel findings suggest that ovaries express and secrete a variety of different exosomes containing miRNAs that might play an important role in the stability of transcriptome in gonads and diversity of different distant organs. Based on our findings we propose the general hypothesis is that young ovaries increase healthspan and longevity by secreting exosomes enriched with miR-181b-5p and miR-1249-3p, which target genes involved in insulin signaling. In the proposed studies we will investigate the effects of ovaries from young or long-living animals on the production and secretion of putative pro-longevity miRNA and the mechanism by which these miRNAs modulate high insulin sensitivity during aging. To test our hypothesis we propose three specific aims: Specific Aim 1: Determine if ovaries serve as a source of circulating factors that improve healthspan. Specific Aim 2: Assess the influence of ovarian-derived miRNAs on insulin sensitivity Specific Aim 3: Determine the ovarian secretory pattern of circulating exosomal miRNAs in mice and human ovaries.

我们研究的长期目标是确定年轻卵巢在治疗性青少年生殖中的作用。 携带推定的促长寿microRNA（miRNAs）的外泌体形式的保护因子。与 随着老年人口的不断增长，与年龄有关的疾病，包括代谢性疾病的发病率也在不断上升。 综合征、胰岛素抵抗和糖尿病。健康与健康之间有着牢固的联系。 生殖器官的功能和寿命。重要的是，研究表明，将年轻的卵巢移植到 年老的老鼠可以延缓衰老，寿命延长40%以上。不幸的是， 年轻的卵巢提供这些长寿的好处仍然是不确定的。其中一个可能的好处是 与性激素的增加有关，但也表明，消除性激素 在移植前在卵巢中产生细胞，仍然产生了长寿的好处。重要的是，对于 我们的新发现表明，卵巢表达和分泌多种不同的 含有miRNAs的外泌体可能在性腺转录组的稳定性中发挥重要作用， 不同的远距离器官。根据我们的发现，我们提出的一般假设是，年轻人 卵巢通过分泌富含miR-181 b-5 p和miR-1249- 3 p的外泌体来增加健康寿命和寿命， 其靶向与胰岛素信号有关的基因。在拟议的研究中，我们将调查的影响， 来自年轻或长寿动物的卵巢对推定的促长寿miRNA的产生和分泌的影响 以及这些miRNAs在衰老过程中调节高胰岛素敏感性的机制。来测试我们 假设我们提出三个具体目标： 具体目标1：确定卵巢是否作为改善健康的循环因子的来源。具体 目的2：评估卵巢衍生的miRNAs对胰岛素敏感性的影响 小鼠和人卵巢中循环外泌体miRNA的卵巢分泌模式。

项目成果

Effects of calorie, protein, and branched chain amino acid restriction on ovarian aging in mice.

• DOI: 10.1016/j.repbio.2024.100856
• 发表时间: 2024-01
• 期刊: Reproductive biology
• 影响因子: 2.1
• 作者: G. B. Veiga;B. Zanini;D. N. Garcia;Jéssica D Hense;M. M. Barreto-M.;J. Isola;R. Mondadori;M. Masternak;Michael B Stout;Augusto Schneider