Imaging Dynamic Aspects of Mammary Morphogenesis and Oncogenesis

乳腺形态发生和肿瘤发生的成像动态方面

• 批准号: 7146313
• 负责人: LOLING SONG
• 金额: $ 14.59万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146313
• 关键词: acinar cell

DESCRIPTION (provided by applicant): The long-term objective of the PI is to gain in-depth understanding of a specific area in cell biology such that the PI will be able to define and explore unique biomedical research opportunities using advanced optical biophysical methods. The objective of the proposed project is to understand the dynamics of the morphogenesis of breast epithelial structures by two-photon excitation and fluorescence lifetime imaging microscopy and define the processes that occur prior to and during apoptotic events associated with lumen formation. In addition, I aim to elucidate signaling pathways associated with distinct steps in the morphogenesis of hollow, spherical growth arrested mammary epithelial structures. The majority of benign and malignant breast cancers are characterized by filling of the hollow lumen of the end spheroid structure (or acinus). Preliminary evidence indicates that luminal clearance is at least partially due to selective apoptosis of inner cells due to lack of activation of critical cell signaling proteins. We have found that a dichotomy develops between the outer and inner acinar cells during morphogenesis and that the inner cells become nonresponsive to EGFR stimulation. We hypothesize that apoptosis takes place in the inner cells as a result of deprivation of signals that are important to cell survival. I will investigate the normal processes that are associated with the development of this dichotomy in order to elucidate the mechanisms responsible for the differential apoptosis of inner acinar cells and mechanism whereby tumor cells escape apoptosis and fill the luminal space. Aim 1: To define the precise spatial and temporal dynamics of events involved in acinar morphogenesis and lumen formation in order to understand the temporal and spatial relationships between these processes. Aim 2: To define the specific steps in signaling from EGFR that are defective within the inner acinar cells in order to understand the basis for the absence of signaling responses in these cells. Aim 3: To examine the dynamics of processes associated with activation of oncogenes in acinar structures by inducible activation. The proposed project addresses important issues fundamental to our understanding of normal mammary morphogenesis and breast cancer. The implementation of biophysical imaging approaches in this proposal is aimed at complementing biochemical and molecular investigations. The results from this study will provide new insights into the early events of breast cancer, lead to a better understanding how tumor cells escape cell death in the luminal space, and may provide a basis for therapeutic intervention in cancer.

描述（由申请人提供）： PI 的长期目标是深入了解细胞生物学的特定领域，以便 PI 能够使用先进的光学生物物理方法定义和探索独特的生物医学研究机会。该项目的目标是通过双光子激发和荧光寿命成像显微镜了解乳腺上皮结构形态发生的动态，并定义与管腔形成相关的细胞凋亡事件之前和期间发生的过程。此外，我的目标是阐明与中空、球形生长停滞的乳腺上皮结构的形态发生中的不同步骤相关的信号传导途径。 大多数良性和恶性乳腺癌的特征是末端球状结构（或腺泡）的中空腔被填充。初步证据表明，管腔清除至少部分是由于关键细胞信号蛋白缺乏激活而导致内部细胞选择性凋亡。我们发现，在形态发生过程中，外部和内部腺泡细胞之间出现二分法，并且内部细胞对 EGFR 刺激变得无反应。我们假设细胞凋亡发生在内部细胞中，这是由于对细胞生存重要的信号被剥夺造成的。我将研究与这种二分法的发展相关的正常过程，以阐明内部腺泡细胞差异性凋亡的机制以及肿瘤细胞逃避凋亡并填充管腔空间的机制。目标 1：定义腺泡形态发生和腔形成所涉及事件的精确空间和时间动力学，以了解这些过程之间的时间和空间关系。目标 2：定义内部腺泡细胞内有缺陷的 EGFR 信号传导的具体步骤，以便了解这些细胞中缺乏信号传导反应的基础。目标 3：通过诱导激活检查与腺泡结构中癌基因激活相关的过程的动态。 拟议的项目解决了我们理解正常乳房形态发生和乳腺癌的重要问题。该提案中生物物理成像方法的实施旨在补充生化和分子研究。这项研究的结果将为乳腺癌的早期事件提供新的见解，使人们更好地了解肿瘤细胞如何在腔内逃避细胞死亡，并可能为癌症的治疗干预提供基础。