Characterization & Prevention of Chemotherapy-Induced Damage to Ovarian Reserve

表征

• 批准号: 9412853
• 负责人: KUTLUK H OKTAY
• 金额: $ 47.45万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9412853
• 关键词: ATM Signaling Pathway; Affect; Aging; Apoptotic; BRCA1 Mutation; BRCA1 gene; Breast Cancer Patient; Cancer Survivor; Cells; Ceramides; Cessation of life; Chemotherapy-Oncologic Procedure; Clinical; Clinical Research; Code; Collaborations; Complementary DNA; Confocal Microscopy; Coupled; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Gene; Development; Effectiveness; Event; Gene Expression; Genes; Genotoxic Stress; Germ Cells; Goals; Grant; Health; Human; In Situ Hybridization; Injections; Lasers; Lead; Life; Longevity; Measurement; Mediating; Memorial Sloan-Kettering Cancer Center; Mus; Mutant Strains Mice; Mutation; Oocytes; Ovarian; Ovarian Follicle; Pathway interactions; Patients; Play; Population; Predisposition; Prevention; Primordial Follicle; Proteins; Public Health; Quality of life; Quantitative Reverse Transcriptase PCR; RNA Interference; Reproduction; Resistance; Role; Serum; Source; Techniques; Testing; Time; Tissues; Transgenic Organisms; Translating; Translational Research; Woman; Work; Xenograft Model; Xenograft procedure; brca gene; cancer therapy; chemotherapy; density; ds-DNA; experimental study; fertility preservation; gene function; gene repair; genotoxicity; high risk; inhibitor/antagonist; knock-down; malignant breast neoplasm; member; mouse model; mutant; mutation carrier; novel; ovarian damage; ovarian failure; ovarian reserve; overexpression; premature; prevent; prospective; public health relevance; repaired; reproductive; response; sphingosine 1-phosphate; stem; translational medicine

DESCRIPTION (provided by applicant): Cancer therapy-induced ovarian failure is a significant public health problem with potentially 1% of population being affected over reproductive life span. Our overall goal is to understand and prevent the damage caused by such treatments. In the previous grant period we made significant discoveries which set the tone for the next grant period. We discovered that gonadotoxic chemotherapeutics result in primordial follicle death primarily by causing double strand (DSB) DNA breaks, and in response to this insult, oocytes mount an ATM- mediated DNA DSB repair response (Aging, 2011). This response may enable some primordial follicles to survive chemotherapy. Furthermore, we found that DNA DSB repair response is critical in the way oocytes mitigate genotoxic insult and aging, and that women who are deficient in DNA DSB repair, specifically BRCA1- mutation carriers, maybe prone to prematurely depleting their ovarian reserve (Science Translational Medicine, 2013). In addition, we showed that S1P, a naturally occurring ceramide death-pathway inhibitor, reduces chemotherapy-induced primordial follicle death in human ovarian xenografts (Human Reproduction 2014). Stemming from these revelations and the DNA DSB repair response being the unifying theme, our specific aims for the renewal application are: 1. To determine if BRCA-mutation carriers are more prone to chemotherapy-induced ovarian follicle loss because of their inherent deficiency of DNA DSB repair; 2. To reveal the mechanisms by which some primordial follicles are able to survive chemotherapy insult; 3. To understand how S1P protects human ovarian primordial follicle pool. To achieve these aims we will utilize clinical studies, single cel real time PCR as well as microarray strategies, in situ hybridization, gene interference, coupled with human ovarian xenografting and laser capture approaches. While the studies are primarily translational and will utilize human material, mouse models will also be used to strengthen the mechanistic work.

描述（由申请人提供）：癌症治疗引起的卵巢功能衰竭是一个重大的公共卫生问题，可能有1%的人口在生殖寿命期间受到影响。我们的总体目标是了解和预防此类治疗造成的损害。在上一个资助期，我们取得了重大发现，为下一个资助期定下了基调。我们发现，性腺毒性化疗药物主要通过引起双链（DSB）DNA断裂导致原始卵泡死亡，并且响应于这种损伤，卵母细胞产生ATM介导的DNA DSB修复反应（Aging，2011）。这种反应可能使一些原始卵泡能够在化疗中存活下来。此外，我们发现DNA DSB修复反应在卵母细胞减轻遗传毒性损伤和衰老的方式中至关重要，并且DNA DSB修复缺陷的女性，特别是BRCA 1突变携带者，可能倾向于过早耗尽其卵巢储备（Science Translational Medicine，2013）。此外，我们发现S1 P是一种天然存在的神经酰胺死亡途径抑制剂，可减少人卵巢异种移植物中化疗诱导的原始卵泡死亡（Human Reproduction 2014）。源于这些启示和DNA DSB修复反应是统一的主题，我们的具体目标更新申请是：1。确定BRCA基因突变携带者是否因DNA DSB修复的先天缺陷而更容易发生化疗诱导的卵泡丢失; 2.揭示某些原始卵泡能够在化疗损伤后存活的机制; 3.了解S1 P对人卵巢原始卵泡池的保护作用。为了实现这些目标，我们将利用临床研究，单细胞真实的时间PCR以及微阵列策略，原位杂交，基因干扰，加上人类卵巢异种移植和激光捕获方法。虽然这些研究主要是翻译性的，并将利用人类材料，但小鼠模型也将用于加强机械工作。