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: 7482474
• 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/7482474
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acinar Cell; Acinus organ component; Address; Adhesives; Apical; Apoptosis; Apoptotic; Area; Benign; Biochemical; Biomedical Research; Breast; Caspase; Cell Death; Cell Survival; Cell-Cell Adhesion; Cells; Cellular biology; Complement; DNA Sequence Rearrangement; Defect; Depth; Detection; Development; Development Polarity; EGF gene; Epidermal Growth Factor Receptor; Epithelial; Event; Fluorescence; Genes; Growth; Image; Investigation; Lead; Malignant - descriptor; Malignant Neoplasms; Mammary gland; Methods; Microscopy; Mitochondria; Molecular; Morphogenesis; Oncogene Activation; Optics; Pathway interactions; Permeability; Process; Receptor Activation; Relative (related person); Research Personnel; Signal Pathway; Signal Transduction; Signaling Protein; Structure; Therapeutic Intervention; Time; base; deprivation; in vivo; insight; malignant breast neoplasm; neoplastic cell; programs; receptor; response; spatial relationship; tumorigenesis; two-photon

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的长期目标是对细胞生物学中特定领域的特定区域进行深入了解，以便PI能够使用先进的光学生物物理方法来定义和探索独特的生物医学研究机会。拟议项目的目的是通过两光子激发和荧光寿命成像显微镜来了解乳腺上皮结构的形态发生的动力学，并定义与腔形成相关的凋亡事件之前和期间发生的过程。此外，我旨在阐明与空心，球形生长停滞乳腺上皮结构的形态发生相关的信号通路。 大多数良性乳腺癌和恶性乳腺癌的特征是填充末端球体结构（或acinus）的空心腔。初步证据表明，由于缺乏临界细胞信号蛋白的激活，腔清除至少部分是由于内部细胞的选择性凋亡。我们发现，形态发生过程中外部和内部腺泡细胞之间发生二分法，并且内部细胞对EGFR刺激无反应。我们假设凋亡发生在内部细胞中，这是由于对细胞存活很重要的信号而导致的。我将研究与该二分法开发相关的正常过程，以阐明负责内部腺泡细胞差异凋亡的机制以及肿瘤细胞逃脱凋亡并填充腔室空间的机制。目的1：定义参与腺泡形态发生和管腔形成的事件的精确空间和时间动态，以了解这些过程之间的时间和空间关系。目标2：定义来自EGFR的信号传导的特定步骤，这些步骤在内部腺泡细胞内有缺陷，以了解这些细胞中没有信号反应的基础。目标3：检查与诱导性激活在腺泡结构中激活癌基因相关的过程的动力学。 拟议的项目解决了我们对正常乳腺形态发生和乳腺癌的理解至关重要的重要问题。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，从而更好地了解肿瘤细胞如何逃脱腔内空间中的细胞死亡，并可能为癌症的治疗干预提供基础。