Functional Analysis of Endometrial Stem/Progenitor Cells

子宫内膜干/祖细胞的功能分析

基本信息

批准号：
7978454
负责人：
James K Pru
金额：
$ 21.41万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7978454
关键词：
A Mouse Adult Affect Architecture Area Birth Blood Cells Bone Marrow Bone Marrow Transplantation Cell physiology Cells Cellular biology Cervix Uteri Conceptions Decidual Cell Reactions Development Developmental Process Diagnosis Differentiation and Growth Endometrial Endometrial Carcinoma Endometrial Cycles Endometrium Epithelial Epithelium Estrous Cycle Etiology Event Exhibits Female Fertility Fibroblasts Functional disorder Goals Growth Gynecologic Pathology Human Implant Infertility Infusion procedures Label Link Maintenance Mammalian Oviducts Mammals Maps Menstrual cycle Menstruation Morbidity - disease rate Myometrial Natural regeneration Organ Ovarian Ovary Parabiosis Pathology Pelvic Pain Physiologic pulse Physiology Plastics Play Pregnancy Pregnancy Maintenance Pregnancy loss Preparation Process Quality of life Recruitment Activity Recurrence Reproduction Residual state Rodent Role Spontaneous abortion Stem Cell Research Stem cells Stromal Cells Testing Therapeutic Intervention Tissues Transgenic Mice Transplantation United States Uterine Diseases Uterus Vagina Woman adult stem cell aged body system endometriosis human female in vivo male migration mortality mouse model nonhuman primate postnatal programs public health relevance regenerative repaired reproductive research study stem stem cell biology steroid hormone tissue regeneration

项目摘要

DESCRIPTION (provided by applicant): Uterine disease is an extremely common factor affecting the quality of life and morbidity/mortality of the human female. Each year, more than 35,000 women in the US are diagnosed with endometrial cancer; and endometriosis affects up to 15% of reproductive aged women and often results in infertility. Further, inadequate preparation of the uterine lining during early gestation is thought to contribute to recurrent spontaneous pregnancy loss. It is clear that stem cells coordinate developmental and tissue renewal processes during the construction and maintenance of most organs. Yet there are almost no studies of stem cells in the development of the uterus, an organ that undergoes perhaps the most extensive proliferative changes and developmental remodeling in adult mammals. We hypothesize that endogenous endometrial stem/progenitor cells play a functional role in the cyclic changes within the uterus. Our experimental efforts involving bone marrow transplantation, peripheral blood cell infusions and parabiosis have collectively ruled out the likelihood that bone marrow contributes stem cells to uterine tissue architecture as has been suggested by others. Pulse- chase experiments using H2B:GFP transgenic mice and fate mapping studies revealed the identity of long-term label retaining cells (LRC) in the glandular epithelium and stromal compartment nearest the stromal:myometrial interface. A mouse model of endometrial regression and regeneration reveals that despite complete loss of the luminal epithelium following uterine decidualization, residual glandular tissue is sufficient to completely replace all epithelial tissue, an event that occurs in the absence of ovarian derived steroid hormones. Ongoing studies involving isolation and in vivo transplantation will test the stem cell activity of these putative stromal and epithelial adult stem cells. The long term goal of this proposal is to establish a framework with which to build upon as we begin to understand how endometrial stem cells contribute to normal uterine development and fertility, as well as to uterine diseases like endometriosis and endometrial cancer when stem cell function goes awry. PUBLIC HEALTH RELEVANCE: Dysfunction of the uterus is a common factor affecting fertility, the quality of life, and morbidity/mortality of the human female. Each year, more than 35,000 women in the United States are diagnosed with endometrial cancer (fourth most frequent among women), and endometriosis, another debilitating uterine disease that often results in severe pelvic pain and infertility, affects up to 15% of all reproductive aged women. Recurrent pregnancy loss, occurring in an estimated 25-60% of all mammalian conceptions, is thought to occur in part because of faulty preparation of the uterine lining during early pregnancy. Our understanding of these uterine pathologies, and in particular their etiology, is at best limited. Normal uterine function, and thus successful pregnancy, is dependent on normal cycles of endometrial growth, differentiation, regression (menses) and regeneration. We hypothesize that stem cells are responsible for maintenance of this uterine cycle and have proposed to isolate and characterize endometrial stem cells. The long-term goal of our proposed studies will be to demonstrate a causal link between faulty uterine stem cell function and gynecologic pathologies that impact negatively on fertility and quality of life in women.

描述（由申请人提供）：子宫疾病是影响人类女性生活质量和发病率/死亡率的极为普遍因素。每年，美国有35,000多名妇女被诊断出患有子宫内膜癌；子宫内膜异位症影响多达15％的生殖老年妇女，并且经常导致不孕症。此外，妊娠期期间子宫内壁的准备不足被认为会导致复发性自发怀孕丧失。显然，干细胞在大多数器官的构建和维护过程中协调发育和组织更新过程。然而，几乎没有研究干细胞在子宫的发育中，这是一种可能是成年哺乳动物中最广泛的增殖变化和发育重塑的器官。我们假设内源性内源性茎/祖细胞在子宫内的环状变化中起功能。我们涉及骨髓移植，外周血细胞输注和抛物线症的实验性努力，总体排除了骨髓对子宫组织结构贡献干细胞的可能性，正如其他人所建议的那样。使用H2B：GFP转基因小鼠和命运图研究的脉搏追逐实验揭示了在腺体上皮和基质室中长期标记固定细胞（LRC）的身份，其肌层界面最接近。子宫内膜回归和再生的小鼠模型表明，尽管子宫裂解后腔上皮完全丧失，但残留的腺组织足以完全替代所有上皮组织，这种情况在没有卵巢衍生的类固醇激素的情况下发生。正在进行的涉及分离和体内移植的研究将测试这些假定的基质和上皮成人干细胞的干细胞活性。该提案的长期目标是建立一个框架，因为我们开始了解子宫内膜干细胞如何促进正常的子宫发育和生育能力，以及子宫内膜异位症和子宫内膜癌（当干细胞功能都出现问题时）等子宫疾病。公共卫生相关性：子宫功能障碍是影响生育能力，生活质量以及人类女性的发病率/死亡率的常见因素。每年，美国有35,000多名女性被诊断出患有子宫内膜癌（在女性中最常见的第四名）和子宫内膜异位症，这是另一种使子宫疾病造成的令人衰弱的子宫疾病，通常会导致严重的骨盆疼痛和不育，最多影响所有生殖老年女性的15％。复发性怀孕丧失估计发生在所有哺乳动物概念的25-60％中，部分原因是由于在怀孕初期的子宫内膜制备错误而发生。我们对这些子宫病理，尤其是其病因的理解充其量是有限的。正常的子宫功能，因此成功妊娠取决于子宫内膜生长，分化，回归（月经）和再生的正常周期。我们假设干细胞负责维持该子宫周期，并提出孤立和表征子宫内膜干细胞。我们拟议的研究的长期目标是证明子宫干细胞功能和妇科病理学的因果关系，从而对女性的生育能力和生活质量产生负面影响。