Age-related shifts in epithelial lineages and tissue homeostasis in mammary gland

乳腺上皮谱系和组织稳态的年龄相关变化

• 批准号: 8516430
• 负责人: Mark A LaBarge
• 金额: $ 44.74万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516430
• 关键词: Affect; Age; Aging; Aging-Related Process; Algorithms; Alveolus; Architecture; Atlases; Attention; Basement membrane; Benign; Biological; Biomedical Engineering; Breast; Breast Cancer Risk Factor; Cell Aging; Cell Culture Techniques; Cell Lineage; Cells; Cellular biology; Collagen; Collection; Connective Tissue; Data; Elderly; Employee Strikes; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Estrogen Receptors; Exhibits; Fatty acid glycerol esters; Future; Gatekeeping; Gene Mutation; Genomics; Gland; Goals; Histology; Homeostasis; Human; Image; Image Analysis; In Vitro; Incidence; Individual; Knowledge; Laboratories; Lasers; Libraries; Life; Longevity; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary gland; Measures; Microdissection; Microscopy; Modeling; Molecular; Molecular Profiling; Mutation; Myoepithelial; Myoepithelial cell; Normal tissue morphology; Oncogenes; Organoids; Pancreas; Patients; Phenotype; Population; Predisposition; Property; Prostate; Research; Resources; Sampling; Specimen; Telomerase; Time; Tissues; Tumor Bank; Woman; age related; aged; breast density; cell age; design; in vivo; loss of function; malignant breast neoplasm; malignant state; mammary epithelium; normal aging; novel; older women; progenitor; prophylactic; receptor expression; regenerative; self organization; stem; telomere; trait; tumor; tumorigenesis; young woman

DESCRIPTION (provided by applicant): The association of aging with increased incidence of breast cancer is well known, but little understood. Emphasis has been placed on differences among tumors as a function of age, while considerably less attention is given to changes that occur normally in mammary epithelium during the process of aging, which may facilitate tumorigenesis. A commonly invoked mechanism to help explain age-related cancer is the gradual accumulation of mutations and epigenetic changes. However, it is known that cells harboring even the strongest oncogenes can appear phenotypically normal when held in check by normal tissue architecture. Most tissues exhibit functional and regenerative decline with advancing age. Our over-arching hypothesis is that age-associated breast cancer may partly result from loss-of-function alterations, e.g. changes to structural and architectural gatekeepers that maintain normal tissue organization and polarity, which leads to deleterious imbalances of or changes in the activity of progenitors and more differentiated epithelial lineages. That the majority of women live healthy cancer-free lives suggests age-related changes to the breast tissue are usually benign, but in cases when deleterious genomic changes also are present the combination with deteriorating microenvironments may be catastrophic. Some age-associated changes in breast includes increased fat and estrogen receptor expression; decreased connective tissue, numbers of alveoli and overall breast density; changes in collagen-type expression, and discontinuities in the basement membrane of the mammary gland. We simply do not know what impact these changes have on epithelial cell biology or on the architecture and organization with the gland. This proposal will use the Human Mammary Epithelial Cell (HMEC) Aging Resource, which is a large collection of normal finite-life span HMEC strains that were established from patients ranging in age from 16-91, to perform heretofore impossible quantitative and functional analysis of normal HMEC as a function of age. Changes in populations and functional properties of stem, progenitor, and more differentiated lineages will be measured, as will the ability of HMEC to form and maintain a normal organized bilayered architecture, an ability that is lost early in tumorigenesis, is affected by the aging process. In parallel with our functional analysis, we will perform an automated quantitative analysis of over 500 histological sections of normal breast to generate an atlas of aging-associated changes in the breast tissue, and to identify changes in organization in vivo among the different HMEC lineages. Our goal is to identify potentially deleterious changes that occur in most women during the aging process that could be targets of future prophylactic and preventative strategies.

描述（由申请人提供）：衰老与乳腺癌发病率增加的关联是众所周知的，但鲜为人知。重点已放在肿瘤之间的差异作为年龄的函数上，而对通常在乳腺上皮中通常发生的变化的关注大大降低了，这可能促进肿瘤发生。有助于解释与年龄相关的癌症的一种普遍调用的机制是突变和表观遗传变化的逐渐积累。但是，众所周知，当受正常组织结构检查时，即使有最强的肿瘤基因的细胞也可能在表型上看起来正常。随着年龄的增长，大多数组织表现出功能和再生下降。我们的统计假设是，与年龄相关的乳腺癌可能部分是由于功能丧失改变，例如改变了维持正常组织组织和极性的结构和建筑守门人的变化，这会导致祖细胞活性和更分化的上皮谱系的有害失衡或变化。大多数女性过着健康的无癌生活表明与年龄相关的乳腺组织的变化通常是良性的，但是在有害基因组变化的情况下，与恶化的微环境的结合可能是灾难性的。乳房中某些与年龄相关的变化包括脂肪和雌激素受体表达增加。结缔组织减少，肺泡的数量和整体乳房密度；胶原型表达的变化和乳腺基底膜的不连续性的变化。我们根本不知道这些变化对上皮细胞生物学或与腺体的建筑和组织有什么影响。该提案将使用人类乳腺上皮细胞（HMEC）老化资源，该资源是大量正常有限寿命跨度HMEC菌株，这些菌株是从16-91岁的患者中确定的，以迄今为止无法进行正常HMEC作为年龄功能的正常HMEC的不可能的不可能的定量和功能分析。将测量茎，祖细胞和更多分化谱系的种群和功能特性的变化，HMEC形成和维持正常有组织的双层结构的能力也将受到衰老过程的影响。与我们的功能分析同时，我们将对超过500个正常乳腺组织学部分进行自动定量分析，以产生乳腺组织中衰老相关变化的地图集，并确定不同HMEC谱系中组织的组织变化。我们的目标是确定大多数妇女在衰老过程中可能是未来预防和预防策略的目标的潜在有害变化。