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少年生产中的作用 外泌体形式的保护因子携带推定的丙糖维特microRNA（miRNA）。与 越来越多的老年人人口，与年龄有关的疾病（包括代谢）的发生率越来越大 综合征，胰岛素抵抗和糖尿病。健康与 生殖器官和寿命的功能。重要的是，已经表明将年轻卵巢移植到 老鼠会延迟衰老，并将寿命延长40％以上。不幸的是，详细的机制 年轻的卵巢提供这些寿命福利仍然不确定。可能的好处之一可能是 与增强的性激素产生有关，但也证明了消除性激素 移植前在卵巢中产生细胞，仍会产生促糖益处。重要的是， 该提案的目的我们的新发现表明卵巢表达并分泌各种不同的不同 含有miRNA的外泌体可能在性腺中转录组的稳定性中起重要作用 不同远处器官的多样性。根据我们的发现，我们提出了一般假设是年轻的 卵巢通过分泌具有miR-181b-5p和miR-1249-3p的外泌体来增加健康状态和寿命 哪些靶基因参与胰岛素信号传导。在拟议的研究中，我们将研究 来自年轻动物或长寿动物的卵巢在推定的pro-longevity mirna的生产和分泌上 这些miRNA在衰老过程中调节高胰岛素敏感性的机制。测试我们的 假设我们提出了三个具体目标： 特定目的1：确定卵巢是否是改善健康范围的循环因素的来源。具体的 目标2：评估卵巢衍生的miRNA对胰岛素敏感性特定目的的影响3：确定 小鼠和人类卵巢中循环外泌体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