BLR&D Research Career Scientist Award Application

项目概要： 我目前的研究重点是了解乳腺癌发生的机制， 进步。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，但我们认为， 评估乳腺癌作为一种影响多器官功能的全身性疾病。乳腺癌- 相关的死亡不仅仅是由于癌细胞转移到远处器官或对治疗的抵抗 而且还由于其对骨骼和骨骼肌的癌症有害作用。不像肺和胰腺 癌症，其中癌症导致衰弱性体重减轻和恶病质、身体 大多数乳腺癌患者的外观保持“正常”。然而，骨骼肌质量的损失， 体重明显减轻是很常见的，这种肌肉质量的减轻与不良结果有关。在我们 VA资助的研究，我们正在分子解剖癌症相关的骨骼肌变化， 骨骼肌变化的生物标志物，用于早期检测癌症诱导的全身效应， 限制癌症对骨骼肌影响的方法。这些研究扩展到其他癌症 包括膀胱癌、肺癌、胰腺癌和头颈癌。我们观察到特定的分子差异， 男性和女性患同一类型癌症的骨骼肌。因此，存在性别依赖性差异 在癌症进展途径中，正在探索开发可能适用于男性的治疗方法， 得了癌症由于VA治疗的患者中有11%是癌症幸存者，因此我们的研究具有重要意义 改善退伍军人事务部的医疗保健 实验室的其他研究是：1）与乳腺癌转移相关的机制 和治疗耐药性; 2）正常乳腺生物学中的遗传祖先依赖性变异; 3）定义 使用单细胞基因组学的乳腺癌起源细胞，4）暴露于生理外氧的影响 对正常和癌症干细胞的影响; 5）通过了解最早的癌症干细胞， 乳腺癌发生的时间。这些研究与VA资助的研究没有重叠， 独立机构。这些持续努力的目标是全面了解乳腺癌 发展和进展，并进一步有助于个性化乳腺癌表征， 治疗我们的目标是开发基于细胞来源的乳腺癌分类方法，并探索治疗方法。 基于基因组畸变的模式。我们对生理外氧作用的研究有望 改变生物标志物发现的组织收集方法。该实验室在过去一年中一直非常富有成效， 自2015年以来发表了29篇论文，包括最近在著名期刊上发表的两篇合著论文 Nature和Nature Communications以及在Cancer等期刊上发表的多篇资深作者论文 Research.我们的出版物已收到超过15，100次引用，H因子为62。体制 基础设施，无论是在IU和VA，以及机构内外的合作和持续的 过去23年的校外资助使我们能够实现这些目标。 除了研究，我还参与指导初级教师，博士后研究员，研究生 学生，医学生，高中生和高中教师在过去的23个夏季研究 年（>50名学员）。我曾在国家和国际各级的各种赠款审查委员会任职， 担任癌症研究等知名期刊的编辑。自2015年以来，我已经邀请了37位 在国家和国际场所的讲座，突出了我们的研究的意义和认可。

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.