Cooperative Multicenter Reproductive Medicine Network (U10)

多中心生殖医学合作网络（U10）

基本信息

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
项目类别：
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

项目摘要

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）：加州大学旧金山分校 (UCSF) 生殖健康中心 (CRN) 具有独特的优势，可以参与多中心生殖医学合作网络 (RMN)。 CRN 采用多学科方法来护理患者，并将受益于 Kaiser-Permanente San Francisco 和旧金山总医院 (SFGH) 的社区参与。这种伙伴关系提供了强大的实践量，这将有助于受试者注册，并且我们患者的不同种族、民族和社会人口特征将提高其普遍性治疗方案。同样重要的是，我们在临床试验方面拥有领导力和经验，可确保成功。临床研究是将基础科学转化为临床的关键一步，该研究的应用直接影响患者的护理。在过去的四十年里，发达国家的妇女推迟了生育。生育能力随着年龄的增长而下降，35 岁以上女性的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，导致着床失败以及流产和出生缺陷的风险增加。老年不孕症患者的卵母细胞线粒体活性似乎异常，ATP 生成减少，从而限制了正常卵母细胞染色体分离和胚胎发育。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体可能无法正常形成，纺锤体的改变会导致非整倍体胚胎。在老年女性中，数十年来，原始卵泡中的卵丘卵母细胞复合体（COC）暴露于线粒体呼吸产生的低水平活性氧（ROS）中。由此产生的对线粒体 DNA 和参与辅酶 Q10 合成的酶的累积损伤将减少线粒体产生 ATP 的底物。我们假设卵母细胞线粒体功能的改变反映了辅酶 Q10 的可用性随着年龄的增长而减少。如果我们的假设正确，我们也许能够通过给予辅酶 Q10 来增加 ATP 的产生并增加抗氧化活性，从而减少对 COC 的损害，从而部分逆转卵母细胞的衰老。为了检验这一假设，我们提出了一项多中心、安慰剂对照、随机试验，其目的如下：1) 确定补充辅酶 Q10 是否可以缩短卵巢刺激和宫内授精后进行体外受精 (IVF)/胞浆内单精子注射后的分娩时间（胞浆内单精子显微注射）； 2) 确定补充辅酶Q10是否影响卵母细胞发育能力、卵泡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/时间老化以及卵母细胞的发育能力有关。我们的研究在方法上具有创新性，将辅酶 Q10 的大型多中心随机安慰剂对照试验与卵泡的实验室评估相结合，以表征氧化应激 (OS) 和辅酶 Q10 在卵巢衰老中的作用。此外，积极的结果将为女性提供第一种治疗方法，以克服衰老对卵母细胞的影响以及由此导致的怀孕潜力降低。