BLR&D Research Career Scientist Award Application

项目总结： 我目前的研究重点是了解乳腺癌的发病机制和 进步了。虽然许多关于乳腺癌进展的研究都集中在癌细胞生物学上，但我们 评估乳腺癌是影响多器官功能的全身性疾病。乳腺癌- 相关死亡不仅仅是由于癌细胞转移到远处器官或抵抗治疗所致。 但也是由于癌症对骨骼和骨骼肌的有害影响。与肺和胰腺不同 癌症导致衰弱的体重减轻和临床表现恶病质，身体 大多数乳腺癌患者的外貌仍然是“正常的”。然而，骨骼肌质量的损失在没有 明显的体重减轻是非常常见的，这种肌肉质量的损失与不良结局相关。在我们的 VA资助的研究，我们正在从分子上解剖与癌症相关的骨骼肌变化，开发 骨骼肌变化的生物标志物用于癌症诱导的全身效应的早期检测和治疗 限制癌症对骨骼肌影响的方法。这些研究扩展到了其他癌症。 包括膀胱癌、肺癌、胰腺癌和头颈癌。我们观察到了特定的分子差异 患有相同类型癌症的男性和女性的骨骼肌。因此，存在性别依赖的差异 在癌症进展途径上，正在探索开发可能适用于男性的治疗方法 得了癌症。由于在退伍军人管理局接受治疗的患者中有11%是癌症幸存者，我们的研究具有重要意义 在改善退伍军人管理局的医疗保健方面。 实验室中的其他研究是关于1)与乳腺癌转移有关的机制 和治疗抗性；2)正常乳腺生物学中依赖于遗传祖先的变异性；3)定义 用单细胞基因组学研究乳腺癌的起源细胞，4)暴露于外源性氧气的影响 对正常干细胞和癌症干细胞的研究；以及5)通过最早了解制定化学预防策略 乳腺癌发生过程中的事件。这些研究与退伍军人管理局资助的研究没有重叠，由 独立机构。这些正在进行的努力的目标是全面了解乳腺癌 发展和进展，并进一步促进乳腺癌的个体化特征和 治疗。我们的目标是开发基于起源细胞的乳腺癌分类方法，并探索治疗方法。 基于基因组像差的模式。我们对外源性氧气影响的研究有望 改变组织收集方法以发现生物标记物。在过去的几年里，这个实验室一直很有成效 自2015年以来发表了29篇论文，其中包括最近在著名期刊上发表的两篇合著者论文 《自然与自然通讯》以及在《癌症》等期刊上发表的几篇资深作者论文 研究。我们的出版物收到了超过15,100次引用，H因子为62。体制上的 信息技术部门和退伍军人管理局的基础设施，以及机构内外的协作和持续 过去23年的外部资金使我们能够实现这些目标。 除了研究，我还参与指导初级教员、博士后研究员、研究生 过去23年的学生、医学生、高中生和高中教师暑期调查 年限(&gt；50名学员)。我曾在国家和国际各级的各种拨款审查委员会任职， 担任著名期刊如《癌症研究》的编辑。自2015年以来，我已经邀请了37人 在国内和国际场合的讲座突出了我们研究的重要性和认可度。

Project summary: My current research is focused on understanding mechanisms by which breast cancer initiates and progresses. While many studies on breast cancer progression are focused on cancer cell biology, we are evaluating breast cancer as a systemic disease that influences the function of multiple organs. Breast cancer- associated deaths are not simply due to metastasis of cancer cells to distant organs or resistance to treatment but also due to its deleterious effects of cancer on bone and skeletal muscle. Unlike lung and pancreatic cancers where cancer leads to debilitating weight loss and clinical appearance of cachexia, physical appearance of most breast cancer patients remains “normal”. However, loss of skeletal muscle mass without overt loss of body weight is very common and this loss of muscle mass is associated with poor outcome. In our VA funded study, we are molecularly dissecting cancer-associated skeletal muscle changes, developing biomarkers of skeletal muscle changes for early detection of cancer-induced systemic effects, and therapeutic modalities to limit the effects of cancer on skeletal muscle. These studies are extended to other cancers including bladder, lung, pancreatic, and head and neck cancers. We observed specific molecular differences in skeletal muscle of men and women with the same type of cancers. Thus, there are sex-dependent differences in cancer progression pathways, which are being explored to develop therapies that may be applicable to men with cancer. Since 11% of patients treated at VA are cancer survivors, our studies have important implications in improving health care at VA. Additional studies in the laboratory are on 1) mechanisms associated with breast cancer metastasis and therapeutic resistance; 2) genetic ancestry-dependent variability in the normal breast biology; 3) defining cell-of-origin of breast cancer using single cell genomics, 4) the impact of exposure to extraphysiologic oxygen on normal and cancer stem cells; and 5) developing chemoprevention strategies by understanding earliest events in breast cancer initiation. These studies have no overlap with VA-funded studies and funded by independent agencies. Goals of these ongoing efforts are to comprehensively understand breast cancer development and progression and to further contribute to individualizing breast cancer characterization and treatment. We aim to develop methods to classify breast cancer based on cell-of-origin and explore therapeutic modalities based on genomic aberrations. Our study on the effects of extraphysiologic oxygen is expected to change the method of tissue collection for biomarker discovery. The laboratory has been very productive over the years with 29 publications since 2015 including two recent co-author publications in prestigious journals Nature and Nature Communications and several senior author publications in journals such as Cancer Research. Our publications have received more than 15,100 citations with H-factor of 62. The institutional infrastructure, both at IU and VA, and collaborations within and outside the institution and continuous extramural funding for the past 23 years enabled us to achieve these goals. In addition to research, I have been involved in mentoring junior faculty, post-doctoral fellows, graduate students, medical students, high school students, and high school teacher summer research for the past 23 years (>50 mentees). I served/serve in various grant review committees at national and international levels and serve as an editor of prestigious journals such as Cancer Research. Since 2015, I have given 37 invited lectures at national and international venues highlighting the significance and recognition of our research.