Project 1: Measuring and Modifying the Human Follicle Environment to Improve In

项目摘要(见说明)：面对癌症诊断，包括放射、手术和化疗在内的生命保护策略可能会损害女性生殖轴的几乎所有方面，导致不孕不育、亚生育或过早更年期。此外，几种情况和疾病状态可能会产生类似的后果。对于女性来说，幸运的是，卵巢具有从标准(即试管受精、ICSI、胚胎库)到调查性(卵巢组织冷冻保存、卵巢移植)的各种生育能力保存选择的潜力。体外卵泡生长是另一项新兴技术，它为患有血液传播恶性肿瘤、不能耐受超生理激素水平、不能推迟治疗或没有精子捐赠者的一部分人带来了巨大的希望。在小鼠体内进行IVFG已经取得了巨大的成功，以至于使用从几乎所有尝试过的方法中获得的配子已经实现了活产。然而，由于卵泡大小、发育、代谢需求和生理生态位等因素的显著差异，这项技术在大型哺乳动物物种中的应用并不是微不足道的。在这个项目中，我们将开发“智能”生物材料，这种材料将为人类卵泡提供自我调节其物理环境的能力，因为它们生长到发育的末期阶段。我们预计，这样的环境将维持卵母细胞及其伴生颗粒细胞的协调生长，这是优化内分泌功能和配子质量所必需的。我们还将开发新的非侵入性卵泡健康内分泌测量方法，通过精确的算法，可以与传统的类固醇和多肽分析结合使用，以预测单个卵泡的成熟度。发育到成熟正确阶段的卵泡将包含最高质量的配子，我们将使用创新的纳牛顿力测量来定量了解在减数分裂过程中在体内和体外产生染色体正常卵子的机制这些实验对人类健康具有广泛的影响，因为染色体正常的卵子是创造健康后代的基本先决条件。我们的目标是以实验为基础，整合三种模式生物--小鼠、奶牛和人类--并跨越多个学科--生殖医学、细胞和分子生物学、生物工程和生物物理学。这一结合将使我们能够以定量的方式推进我们对人类生殖生物学的理解，同时为体外卵泡培养系统可能的临床翻译提供关键见解，以保护患有癌症或其他生殖障碍的年轻患者的生育能力。

PROJECT SUMMARY (See instructions): Life-preserving strategies in the face of a cancer diagnosis, including radiation, surgery, and chemotherapy, can compromise nearly all aspects of the female reproductive axis resulting in infertility, subfertility, or premature menopause. In addition, several conditions and disease states can have a similar consequence. Fortunately for females, the ovary has the potential for diverse fertility preservation options ranging from standard (i.e. IVF, ICSI, embryo banking) to investigational (ovarian tissue cryopreservation, ovarian transplant). In vitro follicle growth is another emerging technology that has tremendous promise for a subset of individuals who have blood-borne malignancies, cannot tolerate supraphysiological hormone levels, cannot delay treatment, or do not have a sperm donor. Tremendous success has been achieved in performing IVFG in the mouse to the degree that live births have been achieved using gametes derived from nearly all methods attempted to date. The translation of this technology to large mammalian species, however, has not been trivial due to significant differences in factors such as follicle size, development, metabolic requirements, and physical niche. In this project, we will develop "smart" biomaterials that will provide human follicles with the ability to self-regulate their physical environment as they grow to terminal stages of development. We anticipate that such an environment will maintain the coordinated growth of the oocyte and its companion granulosa cells, which is required for optimal endocrine function and gamete quality. We will also develop new non-invasive endocrine measures of follicle health that, through a precise algorithm, could be used in association with conventional steroid and peptide assays to predict the maturity of individual follicles. Follicles developed to the right stage of maturity will contain the highest quality gamete, and we will use innovative nanonewton force measurements to quantitatively understand the mechanisms by which a chromosomally normal egg is generated both in vivo and in vitro during meiosis These experiments have broad implications on human health as a chromosomally normal egg is a fundamental pre-requisite to create a healthy offspring. Our aims are based on experiments that integrate three model organisms - mouse, cow, and human - and span multiple disciplines - reproductive medicine, cell and molecular biology, bioengineering, and biophysics. This union will allow us to advance our understanding of human reproductive biology in a quantitative way, and at the same time provide key insights into the possible clinical translation of in vitro follicle culture systems to preserve fertility in young patients with cancer or other reproductive disorders.