Defining Mechanisms of Ovarian Rescue

卵巢拯救的定义机制

基本信息

批准号：
9922135
负责人：
Blanche Capel
金额：
$ 32.71万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-06 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922135
关键词：
Acute Address Adult Aftercare Apoptosis Biology Birth Blood Vessels Cell Death Cells Clinical Contralateral DNA Damage Endothelial Cells Endothelium Epithelial Epithelium Equilibrium Family Feedback Female Fertility Goals Graft Enhancements Growing Follicle Growth Histology Homeostasis Human Immune Infertility Injury Knowledge LGR5 gene Lead Longevity Menopause Methods Modeling Mus Neonatal Neurons Organ Outcome Ovarian Ovarian Follicle Ovary Ovulation Patients Pharmaceutical Preparations Play Population Premature Ovarian Failure Primordial Follicle Quality of life Recovery Reporter Repression Role Side Signal Transduction Source Surface System Testing Tissues Woman Women&apos s Health body system burnout chemotherapy design early onset exhaustion experimental study fetal genetic approach granulosa cell improved macrophage mouse model mullerian-inhibiting hormone neurotransmission novel novel therapeutics outcome forecast paracrine preservation progenitor pup regenerative repaired stem cells therapy design young woman

项目摘要

Many organs are capable of extensive repair after damage, by known mechanisms that can be exploited clinically. By contrast, in spite of the central importance of the ovary for human fertility and women’s health, many important aspects of its basic biology, including its capacity for repair, are poorly understood. For example, ovarian longevity is dependent on the supply of follicles, but how the balance between quiescent versus developing follicles is regulated has not yet been determined. Likewise, it was recently discovered that adult and fetal granulosa cells arise at independent stages from LGR5+ progenitors in the neonatal ovarian surface epithelium (OSE) -‐ but whether these LGR5+ cells can renew adult follicles is not known. Finally, in many organs, vascular, neuronal, and immune cells play critical roles in repair, but their functions in the ovary have not been fully investigated. We recently developed a novel murine model of chemotherapy (CTx)-‐induced infertility and premature ovarian failure (POF). Surprisingly, when we grafted a fragment of a normal ovary to one ovary of a CTx-‐ treated female, grafted females produced multiple litters over the next 5 months, containing normal pups derived from both the host and the donor. Histology revealed that only the grafted ovary was rescued, while the contralateral side degenerated and all follicles were lost. These experiments show that the ovary can be rescued after CTx through signals from a normal ovary. The primary goals of this project are to characterize the mechanisms underlying the loss of all follicles after CTx, and to determine how a small graft from a healthy ovary rescues the host organ system. Our experiments are designed to test three alternative, or complementary, mechanisms of rescue. First, preliminary results suggest that it is the rapidly dividing granulosa cells in growing follicles, and not oocytes, that are the primary target of DNA-‐damaging chemotherapeutic drugs. In Aim 1 we will test whether the loss of granulosa cells in growing follicles leads to de-‐repression of quiescent granulosa cells in primordial follicles, resulting in exhaustion of the reserve pool or “follicle burn out”, and whether signals from the graft block this depletion. In Aim 2, we will test whether LGR5+ cells in the OSE respond to damage and give rise to new granulosa cells after grafting. CTx may interfere with this regenerative activity while signals from the graft may promote it. In Aim 3, we will test whether the graft enhances signals from neural, vascular, or immune cells that can promote repair after injury. Results may lead to new therapies and change the prognosis for women undergoing POF from different causes.

许多器官在损伤后能够通过可在临床上利用的已知机制进行广泛的修复。相比之下，尽管卵巢对人类生育能力和女性健康至关重要，但许多人人们对其基本生物学的重要方面（包括其修复能力）知之甚少。例如，卵巢寿命取决于卵泡的供应，但静止期与发育期之间的平衡如何同样，最近发现成人和胎儿的卵泡调节尚未确定。颗粒细胞在新生儿卵巢表面上皮中的 LGR5+ 祖细胞的独立阶段产生 (OSE) - - 但这些 LGR5+ 细胞是否能够更新成年卵泡最后，在许多器官、血管、神经元和免疫细胞在修复中发挥着关键作用，但它们在卵巢中的功能尚未充分发挥。我们最近开发了一种化疗（CTx）引起的不孕症的新型小鼠模型。令人惊讶的是，当我们将正常卵巢的片段移植到 CTx-‐ 的一个卵巢时。经过治疗的雌性，嫁接的雌性在接下来的 5 个月内产下多窝幼崽，其中包括正常的幼崽来自宿主和供体的组织学结果显示，只有移植的卵巢被保存，而移植的卵巢被保存。对侧退化并且所有卵泡丢失，这些实验表明卵巢可以被挽救。 CTx 后通过正常卵巢的信号该项目的主要目标是表征 CTx 后所有卵泡丧失的机制，并确定来自健康的小移植物如何卵巢拯救宿主器官系统我们的实验旨在测试三种替代方案，或首先，初步结果表明它是快速分裂的颗粒。生长中的卵泡中的细胞，而不是卵母细胞，是 DNA 损伤性化疗药物的主要目标。在目标 1 中，我们将测试生长中的卵泡中颗粒细胞的损失是否会导致静止期的去抑制。原始卵泡中的颗粒细胞，导致储备池耗尽或“卵泡烧坏”，以及是否来自移植物的信号会阻止这种消耗。在目标 2 中，我们将测试 OSE 中的 LGR5+ 细胞是否对此做出反应。移植后损伤并为新的 osa 细胞提供颗粒。CTx 可能会干扰这种再生活动来自移植物的信号可能会促进它。在目标 3 中，我们将测试移植物是否增强来自神经、可以促进损伤后修复的血管或免疫细胞的结果可能会带来新的疗法并改变现状。不同原因导致 POF 的女性的预后。