BONE MATRIX BOUND GROWTH FACTORS BREAST CANCER

描述(申请人描述)：应聘者的研究经历 是在骨细胞生物学领域，她的主要兴趣一直是 生长因子、细胞外基质蛋白与骨髓瘤骨病。这个 应聘者博士后培训即将结束，希望成为一名 独立研究人员，能够指导高质量的学术研究 在她自己的实验室里进行研究。为了做到这一点，她提议成为她的 在骨基质和生长因子方面的专业知识进入乳腺癌领域。 乳腺癌经常转移到骨骼，并经常导致骨骼 破坏，给患者带来令人衰弱的并发症。建议数 研究基于骨基质结合生长因子的假设 在将骨骼定义为生长的肥沃土壤方面发挥关键作用 乳腺癌细胞。这些研究定义了一个关注的领域 与她的导师分开的候选人，但允许她画 从博士后培训中获得的专业知识。这个 候选人将在第一年和第二年从她那里获得额外的培训 联合赞助商，Theresa Guise博士和Lynda Bonewald，为她的参赛做准备 作为一名富有成效的研究人员，他进入了乳腺癌领域。到了第三年 候选人将是一名完全独立的调查员。候选人是 目前在内分泌科，该科有一大群 是乳腺癌领域专家的工作人员。因此，将有 有很多机会与高级同事进行专业互动，以及 用于介绍和讨论数据。候选人也将成为一名 圣安东尼奥癌症研究所成员，并从资源中受益 由该组织提供。拟议研究的目标是 研究骨基质结合转化生长因子β的作用 (TGFβ)对转移性乳腺肿瘤骨破坏能力的调节作用 癌细胞通过刺激甲状旁腺相关激素的产生 蛋白质(PTHrP)，一种强大的骨吸收因子。具体目标1将 检查骨基质衍生的转化生长因子β是否负责刺激 乳腺癌细胞产生甲状旁腺素受体，从而增加 癌症相关的骨质破坏。这将通过在体外和体内完成。 活体模型。具体目标2和3将研究分子机制。 用于乳腺癌细胞释放骨基质结合的转化生长因子β。最初 将确定是否通过蛋白水解性裂解发生释放 潜在的转化生长因子β结合蛋白(LTBP-1)与骨细胞的情况一样。 然后，LTBP1中的蛋白水解性切割位点将被定位和拮抗 旨在抑制LTBP1的切割和由此导致的释放的多肽 骨基质来源的转化生长因子β。特定目标4将检查乳房的能力 癌细胞激活基质释放的潜伏的转化生长因子β。这项研究将 为研究乳房之间复杂的相互作用提供了一种新的途径 癌细胞与骨骼微环境的关系及其可能导致的发展 减少与癌症相关的骨质破坏的新疗法。

DESCRIPTION (Applicant's Description): The candidate's research experience is in the field of bone cell biology, where her main interests have been in growth factors, extracellular matrix proteins and myeloma bone disease. The candidate is at the end of her postdoctoral training and wishes to become an independent investigator, capable of directing high quality academic research in her own laboratory. To do this, she proposes to being her expertise in bone matrix and growth factors into the field of breast cancer. Breast cancer frequently metastasizes to bone and often causes bone destruction, with debilitating complications for the patient. The proposed studies are based on the hypothesis that bone matrix-bound growth factors play a key role in defining bone as a fertile ground for the growth of breast cancer cells. These studies define an area of interest for the candidate which is separate from that of her mentors, but allows her to draw from the expertise she has gained from her postdoctoral training. The candidate would obtain additional training during years 1 and 2 from her co-sponsors, Drs. Theresa Guise and Lynda Bonewald, to prepare her for entry into the field of breast cancer as a productive researcher. By year 3 the candidate will be a fully independent investigator. The candidate is currently in the Division of Endocrinology, which has a large group of workers who are experts in the field of breast cancer. Thus there will be many opportunities for professional interactions with senior colleagues, and for presentation and discussion of data. The candidate would also become a member of the San Antonio Cancer Institute and benefit from the resources provided by this organization. The goal of the proposed studies is to examine the role of bone matrix-bound transforming growth factor beta (TGFbeta) in regulating the bone destructive capacity of metastatic breast cancer cells through stimulating production of parathyroid hormone related protein (PTHrP), a powerful bone resorbing factor. Specific Aim 1 will examine whether bone matrix-derived TGFbeta is responsible for stimulating PTHrP production by breast cancer cells, thereby increasing cancer-associated bone destruction. This will be done using in vitro and in vivo models. Specific Aims 2 and 3 will examine the molecular mechanisms for release of bone matrix-bound TGFbeta by breast cancer cells. Initially it will be determined whether release occurs through proteolytic cleavage of the latent TGFbeta binding protein (LTBP-1) as is the case with bone cells. The proteolytic cleavage sites in LTBP1 will then be mapped and antagonist peptides designed to inhibit cleavage of LTBP1 and the resulting release of TGFbeta from bone matrix. Specific Aim 4 will examine the ability of breast cancer cells to activate matrix-released latent TGFbeta. This study will provide a new approach for studying the complex interactions between breast cancer cells and the bone microenvironment and may lead to the development of new therapies to reduce cancer-associated bone destruction.