Characterization and prevention of Chemotherapy-Induced Damage to Ovarian Reserve

化疗引起的卵巢储备功能损害的特征和预防

基本信息

批准号：
10610413
负责人：
KUTLUK H OKTAY
金额：
$ 71.67万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-15 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610413
关键词：
ATM Signaling Pathway Acceleration Acute Affect Age Aging Apoptotic BRCA mutations BRCA1 gene BRCA2 Mutation BRCA2 gene Biological Assay Biological Models Cancer Etiology Cancer Survivor Cells Ceramides Cessation of life Chemotherapy-Oncologic Procedure Clinical Research Code Collaborations Complementary DNA Confocal Microscopy Coupled DNA Damage DNA Double Strand Break DNA Repair DNA Repair Disorder Diagnosis Double Strand Break Repair FDA approved Fertility Funding Future Gene Expression Genes Genotoxic Stress Germ Cells Grant Growth Health Human Immunohistochemistry In Vitro Individual Infertility Intervention Knowledge Laboratories Lasers Longevity Longitudinal Studies Malignant Neoplasms Mediating Memorial Sloan-Kettering Cancer Center Microinjections Modeling Molecular Mus Mutation Oocytes Ovarian Ovarian Follicle Ovarian aging Ovary Pathway Analysis Pathway interactions Pharmacological Treatment Phase Phosphorylation Predisposition Premature Menopause Prevention Primordial Follicle Proteins Public Health Quality of life Quantitative Reverse Transcriptase PCR RNA Interference Registries Role Serum Small Interfering RNA Source Time Tissues Woman Xenograft Model Xenograft procedure analog cancer therapy chemotherapy clinical translation cohort comparison control efficacy testing experience experimental study fertility preservation genotoxicity gonad function high risk in vivo inhibitor insight knock-down malignant breast neoplasm member mutation carrier novel ovarian damage ovarian reserve pharmacologic preservation prevent repaired reproductive reproductive outcome reproductive senescence sphingosine 1-phosphate transcriptome sequencing translational study

项目摘要

Abstract: Cancer therapy-induced ovarian insufficiency is a major public health problem affecting millions of women over their reproductive life span. Our overarching aim is to understand and prevent the damage caused by cancer treatments and to extend that knowledge to prevent ovarian aging. In the prior period, we successfully achieved all specific aims and showed: i) Breast cancer chemotherapy but not tamoxifen alone induces a significant decline of ovarian reserve; ii) Women with BRCA mutations have fewer primordial follicles in their ovaries, which accumulate more DNA damage with age compared to controls, and, iii) they experience greater ovarian reserve loss after chemotherapy; iv) Selective knock-down of BRCA1 renders oocytes more liable to chemotherapy-induced death; v) Gonadotoxic chemotherapy causes primordial follicle death by inducing DNA double strand breaks (DSBs), which prompts apoptotic follicle death in primordial follicles but not by activation of their growth in the acute phase. In addition, vi) A ceramide-induced death pathway inhibitor Sphingosine-1- Phosphate (S1P) prevents chemotherapy-induced human ovarian follicle death, likely by enhancing the ATM- Pathway. Given the shared mechanisms through DNA damage and repair, these findings opened new avenues in the prevention of chemotherapy-induced damage to gonadal function, and, to reverse, retard or prevent reproductive aging. In the current renewal, we aim to further these studies with the following translational aims: 1. To determine whether the mutations in BRCA1 vs. BRCA2 or other key members of the ATM-mediated DNA DSB Repair Pathway result in the increased susceptibility to chemotherapy-induced ovarian reserve loss and oocyte death in women with breast cancer; 2. To determine differences in the molecular mechanisms of acute and delayed chemotherapy-induced human primordial follicle loss; 3. To test the efficacy and mechanism of an FDA-approved S1P analogue, FTY-720, in the prevention of chemotherapy-induced human ovarian reserve loss. To achieve these translational aims we will combine clinical studies with studies of basic, translational mechanisms using in vivo human ovarian xenograft models, laser-captured individual-oocyte RNA sequencing and single-cell quantitative real-time PCR approaches which evolved in our laboratory during the past funding periods. These translational studies with human material will be mechanistically strengthened with an in vitro mouse oocyte gene-interference and genotoxicity assay (GTA), which we also developed and validated in the past funding periods. This translational proposal will not only expand knowledge of the mechanisms and prevention of chemotherapy- induced ovarian damage but also result in a paradigm shift in our understanding of how ovarian germ cells mitigate genotoxic stress in general. The exploitation of such mechanisms, in addition to leading to new fertility preservation strategies, will provide new insights into future discoveries to moderate reproductive, and potentially, somatic aging.

抽象的：癌症治疗引起的卵巢不足是影响数百万妇女的主要公共卫生问题在他们的生殖寿命上。我们的总体目的是了解和防止癌症治疗并扩展这种知识以防止卵巢衰老。在上一个时期，我们成功实现了所有特定目标并表明：i）乳腺癌化学疗法，但单独的他莫昔芬诱导了A 卵巢储备的大幅下降； ii）BRCA突变的女性的原始卵泡较少卵巢，与对照组相比会积聚更多的DNA损伤，并且，iii）他们经历更大的化学疗法后的卵巢储备损失； iv）brca1的选择性敲击使卵母细胞更容易受到责任化学疗法诱导的死亡； v）促性毒性化学疗法通过诱导DNA导致原始卵泡死亡双链断裂（DSB），这会促使原始卵泡中凋亡的卵泡死亡，但不是通过激活它们在急性阶段的增长。此外，vi）由神经酰胺诱导的死亡途径抑制剂鞘氨酸-1- 磷酸盐（S1P）可防止化学疗法引起的人卵巢卵泡死亡，这可能是通过增强ATM- 路径。鉴于通过DNA损坏和维修的共享机制，这些发现打开了新的途径在预防化学疗法引起的性腺功能损害时，并逆转或预防生殖衰老。在当前的续约中，我们的目标是以以下翻译目的进一步进一步研究： 1。确定BRCA1与BRCA2中的突变或ATM介导的DNA的其他关键成员是 DSB维修途径导致对化学疗法引起的卵巢储备损失的敏感性增加乳腺癌女性的卵母细胞死亡； 2。确定急性分子机制的差异并延迟化疗引起的人类原始卵泡损失； 3。测试一个的功效和机制 FDA批准的S1P类似物，FTY-720，预防化学疗法诱导的人卵巢储备损失。为了实现这些翻译目标，我们将将临床研究与基本，翻译的研究相结合使用体内人卵巢异种移植模型的机制，激光捕获的个体 - 元素RNA测序和单细胞定量实时PCR方法，这些方法在过去的资金中在我们的实验室中进化时期。这些对人类材料的翻译研究将通过体外机械地加强小鼠卵母细胞基因介入和遗传毒性测定（GTA），我们也在该中开发和验证过去的资金期。这项翻译建议不仅将扩大有关机制的知识和预防化学疗法诱导的卵巢损伤，但也导致我们理解的范式转移卵巢生殖细胞一般如何减轻遗传毒性应激。此外，这种机制的开发为了实现新的生育保护策略，将为未来发现提供新的见解生殖，可能是躯体衰老。