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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：
10365036
负责人：
KUTLUK H OKTAY
金额：
$ 74.04万
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/10365036
关键词：
ATM Signaling Pathway Acute Affect Age Aging Apoptotic BRCA mutations BRCA1 gene BRCA2 Mutation BRCA2 gene Biological Assay Biological Models Breast Cancer Etiology Cancer Survivor Cells Ceramides Cessation of life Chemotherapy-Oncologic Procedure Clinical Research Code Collaborations Complementary DNA Confocal Microscopy Coupled DNA DNA Damage DNA Double Strand Break DNA Repair 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 Pharmacology Phase 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 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 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.

摘要：癌症治疗引起的卵巢功能不全是影响数百万妇女的主要公共卫生问题在它们的生殖寿命中。我们的首要目标是了解和防止癌症治疗，并扩大知识，以防止卵巢老化。在过去的一段时间里，我们成功地实现了所有特定的目标，并显示：i）乳腺癌化疗，但不是他莫昔芬单独诱导卵巢储备显著下降; ii）BRCA突变的女性在其卵巢中的原始卵泡较少。卵巢，与对照组相比，随着年龄的增长，它们积累了更多的DNA损伤，以及，iii）它们经历了更大的化疗后卵巢储备功能丧失; iv）BRCA 1的选择性敲低使卵母细胞更容易化疗诱导的死亡; v）性腺毒性化疗通过诱导DNA合成而引起原始卵泡死亡双链断裂（DSB），其促使原始卵泡中的凋亡性卵泡死亡，但不是通过激活他们在急性期的成长。此外，vi）神经酰胺诱导的死亡途径抑制剂鞘氨醇-1- 磷酸盐（S1 P）预防化疗诱导的人类卵泡死亡，可能是通过增强ATM- 通路鉴于DNA损伤和修复的共同机制，这些发现开辟了新的途径在预防化疗引起的性腺功能损伤中，以及逆转、延缓或预防生殖老化在当前的更新中，我们的目标是进一步开展这些研究，并实现以下转化目标： 1.为了确定BRCA 1与BRCA 2或ATM介导的DNA的其他关键成员中的突变是否 DSB修复途径导致对化疗诱导的卵巢储备丧失的易感性增加，乳腺癌妇女的卵母细胞死亡; 2.为了确定急性心肌梗死的分子机制的差异，和延迟化疗诱导的人原始卵泡丢失; 3.为了测试一种 FDA批准的S1 P类似物FTY-720预防化疗诱导的人卵巢储备功能损失为了实现这些转化目标，我们将联合收割机临床研究与基础研究、转化研究相结合。使用体内人卵巢异种移植模型，激光捕获单个卵母细胞RNA测序的机制和单细胞定量实时PCR方法，这些方法是在我们实验室过去的资助中发展起来的。时期这些人类材料的转化研究将通过体外实验在机制上得到加强。小鼠卵母细胞基因干扰和遗传毒性试验（GTA），我们也开发和验证了在过去的融资周期。这一翻译建议不仅将扩大对机制的了解，预防化疗引起的卵巢损伤，但也导致我们理解的范式转变卵巢生殖细胞如何缓解遗传毒性压力的研究。此外，利用这种机制，导致新的生育保护策略，将提供新的见解，未来的发现，以缓和生殖和潜在的身体老化