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

• 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
• 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

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： 癌症治疗导致的卵巢功能不全是影响数百万妇女的主要公共卫生问题 在它们的生殖寿命上。我们的首要目标是了解和预防由 癌症治疗，并扩展这一知识，以防止卵巢老化。在前一段时间里，我们成功地 实现了所有特定目标，并表明：i)乳腺癌化疗而不是单用他莫昔芬可以诱导 卵巢储备显著下降；ii)BRCA突变的女性在其 卵巢，与对照组相比，随着年龄的增长，卵巢积累了更多的DNA损伤，以及，iii)他们经历了更多的 化疗后卵巢储备丧失；iv)选择性下调BRCA1使卵母细胞更容易发生 化疗导致死亡；v)促性腺激素化疗通过诱导DNA导致原始卵泡死亡 双链断裂(DSB)，促进原始卵泡的凋亡性卵泡死亡，但不是通过激活 它们在急性期的生长情况。此外，vi)神经酰胺诱导的死亡途径抑制剂鞘氨醇-1- 磷酸盐(S1P)预防化疗诱导的人卵泡死亡，可能是通过增强ATM- 路径。鉴于DNA损伤和修复的共同机制，这些发现开辟了新的途径 预防化疗引起的性腺功能损害，并逆转、延缓或预防 生殖衰老。在目前的更新中，我们的目标是进一步开展这些研究，实现以下翻译目标： 1.确定BRCA1与BRCA2或ATM介导的DNA的其他关键成员之间的突变 DSB修复途径导致化疗所致卵巢储备丧失的易感性增加 乳腺癌妇女卵母细胞死亡；2.确定急性心肌梗死分子机制的差异 和延迟化疗所致的人原始卵泡丢失；3.检测安慰剂的疗效和作用机制。 FDA批准的S1P类似物FTY-720预防化疗诱导的人卵巢储备 损失。为了实现这些翻译目标，我们将结合临床研究和基础研究，翻译 利用活体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 和单细胞实时定量聚合酶链式反应方法，这是我们实验室在过去的资助期间发展起来的 句号。这些关于人类材料的翻译研究将通过体外实验得到机械加强 小鼠卵母细胞基因干扰和遗传毒性试验(GTA)，我们还在 过去的资助期。这一翻译建议不仅将扩大对机制和 预防化疗引起的卵巢损害也导致了我们理解的范式转变 卵巢生殖细胞如何从总体上减轻遗传毒性应激。利用这种机制，此外， 导致新的生育保护策略，将为未来的发现提供新的见解 生殖和潜在的躯体衰老。