Cooperative Multicenter Reproductive Medicine Network (U10)

多中心生殖医学合作网络（U10）

• 批准号: 8740531
• 负责人: MARCELLE Ivonne CEDARS
• 金额: $ 24.02万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-24 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8740531
• 关键词: Affect; Age; Aging; Ancillary Study; Aneuploidy; Antioxidants; Apoptosis; Basic Science; Biological; Birth Rate; Blast Cell; California; Cell physiology; Cells; Characteristics; Childbirth; Chromosome Segregation; Clinic; Clinical Research; Clinical Trials; Coenzyme Q10; Coenzymes; Communities; Competence; Complex; Congenital Abnormality; Couples; DNA copy number; Development; Embryo; Embryonic Development; Enrollment; Ensure; Enzyme Gene; Enzymes; Evaluation; Fertility; Fertilization; Fertilization in Vitro; First Births; Follicular Fluid; Gene Expression; General Hospitals; Genetic Screening; Infertility; Intracytoplasmic Sperm Injections; Isoprostanes; Laboratories; Leadership; Live Birth; Mediating; Meiosis; Mitochondria; Mitochondrial DNA; Oocyte Donation; Oocytes; Outcome; Ovarian; Ovarian Follicle; Ovarian Stimulations; Oxidative Stress; Pathway interactions; Patient Care; Patients; Positioning Attribute; Pregnancy; Pregnancy Outcome; Pregnancy Rate; Primordial Follicle; Principal Investigator; Production; Reactive Oxygen Species; Reproductive Health; Reproductive Medicine; Research; Respiration; Risk; Role; San Francisco; Series; Spontaneous abortion; Stress; Supplementation; TdT-Mediated dUTP Nick End Labeling Assay; Testing; Time; Translating; Treatment Protocols; Universities; Woman; caspase-3; experience; failure Implantation; gene synthesis; improved; innovation; intrauterine insemination; novel; older women; preimplantation; programs; public health relevance; racial and ethnic; randomized placebo controlled trial; sperm cell; success; ubiquinone 6; young woman

DESCRIPTION (provided by applicant): The Center for Reproductive Health (CRN) at the University of California, San Francisco (UCSF) is uniquely positioned to participate in the Cooperative Multicenter Reproductive Medicine Network (RMN). The CRN takes a multi-disciplinary approach to patient care and will benefit from community involvement of Kaiser-Permanente San Francisco and San Francisco General Hospital (SFGH). This partnership allows a robust practice volume that will facilitate subject enrollment, and the diverse racial, ethnic, and socio-demographic characteristics of our patients will increase the generalizability of treatment protocols. Equally important, we have the leadership and experience in clinical trials to ensure success. Clinical research is a key step in translating basic science to the bedside, and the application of this research directly affects patient care. Over the last four decades, women in the developed world have delayed childbirth. Fertility decreases with age, and live birth rates are lower in women over 35 than in younger women. The decline in live birth rate reflects an increase in oocyte aneuploidy, leading to failure of implantation and increased risk for miscarriages and birth defects. Older infertility patients appear to have abnormal mitochondrial activity in oocytes and reduced production of ATP, which limits normal oocyte chromosomal disjunction and embryo development. Without sufficient ATP, the meiotic spindle, which is crucial for normal chromosome segregation, may not form properly, and altered spindles result in aneuploid embryos. In older women, the cumulus oocyte complex (COC) in primordial follicles is exposed to low levels of reactive oxygen species (ROS) produced by mitochondrial respiration over decades. The resultant cumulative damage to mtDNA and enzymes involved in coQ10 synthesis would reduce the substrate for ATP production by the mitochondria. We hypothesize that altered mitochondrial function in oocytes reflects diminished availability of coQ10 with age. If our hypothesis is correct, we may be able to partially reverse oocyte aging by giving coQ10 to increase ATP production and increase anti-oxidant activity, thereby reducing damage to the COC. To test this hypothesis, we propose a multicenter, placebo-controlled, randomized trial with the following aims: 1) Determine if coQ10 supplementation reduces time to delivery after ovarian stimulation and intrauterine insemination followed by in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI); 2) Determine if coQ10 supplementation affects oocyte developmental competence, intrafollicular oxidative stress, and mitochondrial function; and 3) Determine if oxidative stress in the follicle is relatedto ovarian/chronological aging and to the developmental competence of oocytes. Our study is innovative in its approach - which combines a large multicenter randomized placebo-controlled trial of coQ10, with laboratory evaluation of ovarian follicles, to characterize the role of oxidatve stress (OS) and coQ10 in ovarian aging. Additionally, a positive result would offer women the first treatment to overcome the impact of aging on the oocyte and the resultant lowered pregnancy potential.

描述（由申请人提供）：加利福尼亚大学旧金山分校（UCSF）的生殖健康中心（CRN）独特地参与合作多中心生殖医学网络（RMN）。 CRN采用多学科的患者护理方法，将受益于Kaiser-Permanente旧金山和旧金山综合医院（SFGH）的社区参与。这种伙伴关系允许强大的练习量，可以促进受试者的入学率，并且我们患者的种族，种族和社会人口统计学特征将提高 治疗方案。同样重要的是，我们在临床试验中具有领导和经验，以确保成功。临床研究是将基础科学转化为床边的关键步骤，这项研究的应用直接影响患者护理。在过去的四十年中，发达国家的妇女延迟了分娩。超过35岁的女性的生育能力随着年龄的增长而降低，活产率低于年轻女性。活产率的下降反映了卵母细胞非整倍性的增加，导致植入失败和流产和出生缺陷的风险增加。老年不育症患者似乎在卵母细胞中有异常的线粒体活性和ATP的产生降低，这限制了正常的卵母细胞染色体脱节和胚胎发育。如果没有足够的ATP，对正常染色体分离至关重要的减数分裂纺锤可能无法正确形成，并且纺锤体变化会导致非整倍体胚胎。在老年妇女中，原始卵泡中的卵母细胞复合物（COC）暴露于数十年来通过线粒体呼吸产生的低水平的活性氧（ROS）。涉及COQ10合成的mtDNA和酶的累积损伤将减少线粒体产生ATP的底物。我们假设卵母细胞中线粒体功能的改变反映了COQ10随着年龄的增长的降低。如果我们的假设是正确的，我们可能能够通过给出COQ10来增加ATP产生并增加抗氧化活性来部分逆向卵母细胞衰老，从而减少对COC的损害。为了检验这一假设，我们提出了一个多中心，安慰剂对照，随机试验，其目的：1）确定补充COQ10是否会减少卵巢刺激和宫内授精后的递送时间，然后体外施肥（IVF）/内部体外精子注射（ICSI）（ICSI）； 2）确定补充COQ10是否会影响卵母细胞发育能力，流体内氧化应激和线粒体功能； 3）确定卵泡中的氧化应激是否与卵巢/年代老化以及卵母细胞的发育能力有关。我们的研究在其方法上具有创新性 - 结合了COQ10的大型多中心随机安慰剂对照试验，以及对卵巢卵泡的实验室评估，以表征氧化应激（OS）在卵巢衰老中的作用。此外，阳性结果将为妇女提供第一种治疗方法，以克服衰老对卵母细胞的影响，并降低妊娠潜力。