CAREER: Dysfunctional Osteocyte Mechanoresponse in Tumor-induced Bone Disease

这项教师早期职业发展(Career)奖将确定骨转移性乳腺癌是如何损害特化力敏感型骨细胞(骨细胞)的，以及这种损害如何导致肿瘤诱发的骨病。骨骼是乳腺癌转移的常见部位，这会导致骨丢失、脆性，并最终导致骨折。然而，目前的治疗方法并不针对骨骼健康。机械信号发生在日常体力活动中，众所周知，它可以改善骨骼健康，也可能对肿瘤引起的骨骼疾病具有保护作用。该奖项的工作假设是，骨细胞是更好地科学理解肿瘤引起的骨病的原因和治疗方法的关键。具体地说，这项工作将评估骨转移性乳腺癌是否会导致骨细胞对机械信号的功能失调，从而导致骨丢失。这个项目的结果将扩大关于机械信号和骨细胞在转移癌中的作用的基本知识。该奖项也是跨学科研究的典范。教育目标是培养一支多元化的科学、技术、工程和数学劳动力队伍。来自代表性不足群体的本科生研究人员将通过正规培训获得并利用对科学、技术、工程和数学职业至关重要的研究技能。这项培训将包括有针对性的专业发展和以团队为基础的跨学科项目，这将扩大代表性不足群体中工程师的职业机会。为了检验这一工作假设，该奖项将考察以下方面的影响：1)乳腺癌骨转移对骨细胞导向和机械调节的骨重建机制的影响；2)对乳腺癌细胞施加的机械负荷对骨细胞机械反应的影响；以及3)乳腺癌亚型对骨细胞机械反应的影响。这项研究利用了首席研究员开创的创新的体外/体内实验方法。在体内，受控机械载荷将应用于乳腺癌骨转移的小鼠模型。在体外，骨细胞将在三维培养，并受到多种机械提示(流体流动和基质变形)-这是比最常用的仅二维流动平台的进步。总而言之，这项研究的结果将改变目前对骨转移的理解，确立骨转移肿瘤细胞干扰骨细胞的机械反应，这是导致肿瘤引起的骨疾病和脆性的新机制。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This Faculty Early Career Development (CAREER) award will determine how specialized force-sensing bone cells (osteocytes) are impaired by bone metastatic breast cancer, and how this impairment leads to tumor-induced bone disease. The skeleton is a common site for breast cancer metastasis, which causes bone loss, fragility, and ultimately fractures. However, current therapies do not address bone health. Mechanical signals, which occur during daily physical activity, are well-known to improve to bone health, and they may also be protective against tumor-induced bone disease. The working hypothesis of this award is that osteocytes are the key to a better scientific understanding of the causes and treatments of tumor-induced bone disease. Specifically, this work will evaluate if bone metastatic breast cancer causes a dysfunctional osteocyte response to mechanical signals, which causes bone loss. The results from this project will expand basic knowledge about the role of both mechanical cues and osteocytes in metastatic cancer. This award also exemplifies interdisciplinary research. The Educational Objective is to train a diverse Science, Technology, Engineering, and Mathematics workforce. Undergraduate researchers from under-represented groups will gain and leverage research skills critical to Science, Technology, Engineering, and Mathematics careers through formalized training. This training will include targeted professional development and team-based interdisciplinary projects, which will expand career possibilities for engineers in under-represented groups.To test the working hypothesis, this award will examine the impacts of: 1) breast cancer bone metastasis on bone remodeling mechanisms that are osteocyte-directed and mechanically-regulated, 2) mechanical loading applied to breast cancer cells on the mechanoresponse of osteocytes, and 3) breast cancer subtype on osteocyte mechanoresponse. This research capitalizes on the innovative in vitro/in vivo experimental approaches pioneered by the Principal Investigator. In vivo, controlled mechanical loading will be applied to mouse models of breast cancer bone metastasis. In vitro, osteocytes will be cultured in 3-dimensions and subjected to multiple mechanical cues (fluid flow and matrix deformation) – an advancement over the most commonly used 2-dimension-flow only platforms. In aggregate, results from this research will transform current understanding of bone metastasis by establishing that bone metastatic tumor cells interfere with the mechanoresponse of osteocytes, which is a new mechanism contributing to tumor-induced bone disease and fragility.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.