Characterization & Prevention of Chemotherapy-Induced Damage to Ovarian Reserve

表征

基本信息

批准号：
8815519
负责人：
KUTLUK H OKTAY
金额：
$ 58.06万
依托单位：
NEW YORK MEDICAL COLLEGE
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 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8815519
关键词：
ATM Signaling Pathway Affect Aging Apoptotic BRCA1 Mutation BRCA1 gene Biological Preservation Breast Cancer Patient Breeding Cancer Survivor Cells Ceramides Cessation of life Chemotherapy-Oncologic Procedure Clinical Clinical Research Code Collaborations Complementary DNA Confocal Microscopy Coupled DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Gene Development Effectiveness Event Fertility Gene Expression Genes Genotoxic Stress Germ Cells Goals Grant Health Human In Situ Hybridization Injection of therapeutic agent 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 RNA Interference Reproduction Resistance Role Science Serum Source Tamoxifen Techniques Testing Time Tissues Transgenic Organisms Translating Woman Work Xenograft Model Xenograft procedure cancer therapy chemotherapy density gene function gene repair high risk inhibitor/antagonist knock-down malignant breast neoplasm member mouse model mutant mutation carrier novel ovarian failure overexpression prevent public health relevance repaired reproductive research study response sphingosine 1-phosphate stem translational medicine

项目摘要

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衰竭是一个重大的公共卫生问题，可能1％的人口因生殖寿命而受到影响。我们的总体目标是了解和防止此类治疗造成的损害。在上一个赠款期间，我们进行了重大发现，为下一个赠款期定下基调。我们发现，促性腺毒性化学治疗剂主要是通过引起双链（DSB）DNA断裂而导致原始卵泡死亡，并且为了应对这种侮辱，卵母细胞安装了ATM介导的DNA DNA DSB修复响应（老化，2011年）。这种反应可能使一些原始卵泡能够在化学疗法中生存。此外，我们发现DNA DSB修复反应在减轻遗传毒性的损伤和衰老的方式中至关重要，并且在DNA DSB维修缺乏缺乏的女性中，特别是BRCA1突变载体，可能容易过早地耗尽其卵巢储备（科学转换医学，2013年）。此外，我们表明S1P是一种天然存在的神经酰胺死亡疾病抑制剂，可减少化学疗法诱导的人类卵巢异种移植物中的原始卵泡死亡（Human Roploduction 2014）。由于这些启示和DNA DSB修复响应是统一的主题，我们对更新应用的具体目的是：1。确定BRCA-MON携带者是否更容易容易出现化学疗法诱导的卵巢卵泡损失，因为它们对DNA DSB修复的固有缺陷； 2。揭示某些原始卵泡能够在化学疗法侮辱中生存的机制； 3。了解S1P如何保护人类卵巢原始卵泡池。为了实现这些目标，我们将利用临床研究，单个CEL实时PCR和微阵列策略，原位杂交，基因干扰，再加上人类的卵巢异种和激光捕获方法。虽然研究主要是转化的，并且将利用人类材料，但小鼠模型也将用于增强机械工作。