BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10451507
• 负责人: Harikrishna Nakshatri
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10451507
• 关键词: Address; Affect; African ancestry; Animal Model; Appearance; Atlases; Award; Biological; Biological Markers; Biology; Bladder; Body Weight decreased; Book Chapters; Breast; Breast Cancer Model; Breast Cancer Patient; Breast Epithelial Cells; Breast cancer metastasis; Cachexia; Cancer Patient; Cancer Survivor; Cells; Cellular biology; Cessation of life; Characteristics; Chemoprevention; Chemoresistance; Chronic; Clinic; Clinical; Clinical Trials; Collaborations; Colorectal; Communication; Complement Factor H; Country; Defect; Dependence; Development; Distant; Drug usage; Estrogen Antagonists; Estrogens; Event; Exposure to; Extramural Activities; Faculty; Functional disorder; Funding; Future; Genetic; Genomics; Goals; Grant Review; Growth; Head and Neck Cancer; Health; Healthcare; High School Faculty; High School Student; Hormone Responsive; Hormones; Human; Inflammation; Infrastructure; Institution; International; Journals; Knowledge; Laboratories; Life; Link; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mammary Gland Parenchyma; Maps; Medical Students; Mentors; Methods; MicroRNAs; Mind; Modality; Molecular; Muscle; Muscle function; Muscular Atrophy; Nature; Neoplasm Metastasis; Oncogenes; Organ; Outcome; Oxygen; PI3 gene; PI3K/AKT; Pancreas; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Postdoctoral Fellow; Process; Proto-Oncogene Proteins c-akt; Publications; Published Comment; Publishing; Quality of life; Reporting; Research; Research Personnel; Resistance; Resistance development; Resources; Rest; Review Committee; Risk; Role; Scientist; Screening for cancer; Seeds; Seminal; Sex Differences; Signal Pathway; Skeletal Muscle; Socioeconomic Factors; Systemic disease; Techniques; Technology; Testing; Therapeutic; Tissue Banks; Tissues; Toremifene; Veterans; Woman; Work; anticancer research; base; biomarker discovery; bone; breast cancer progression; cancer cell; cancer initiation; cancer stem cell; cancer type; career; chemotherapy; editorial; effective therapy; epithelial to mesenchymal transition; estrogenic; experience; female sex hormone; genomic aberrations; genomic data; graduate student; health disparity; high risk; improved; inhibitor; lectures; malignant breast neoplasm; member; men; muscle form; nutrition; prevent; programs; receptor; sex; single cell sequencing; skeletal muscle wasting; statistics; stem cells; summer research; symptom management; therapy development; therapy resistant; treatment effect; treatment response; tumor progression

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.

项目摘要： 我目前的研究重点是理解乳腺癌引发和 进展。尽管许多关于乳腺癌进展的研究集中在癌细胞生物学上，但我们是 评估乳腺癌是影响多个器官功能的全身性疾病。乳腺癌- 相关的死亡不仅是由于癌细胞向遥远器官的转移或对治疗的抗性 这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 癌症导致体重减轻和临床外观的癌症，物理 大多数乳腺癌患者的外观仍然“正常”。但是，骨骼肌质量的损失没有 体重的明显损失非常普遍，肌肉质量的损失与不良预后有关。在我们的 VA资助的研究，我们正在分子解剖与癌症相关的骨骼肌变化，发展 骨骼肌变化的生物标志物早期检测到癌症诱导的全身作用和治疗 限制癌症对骨骼肌的影响的方式。这些研究扩展到其他癌症 包括膀胱，肺，胰腺以及头颈癌。我们观察到特定的分子差异 男性和女人的骨骼肌，具有相同类型的癌症。那是有性别差异的 在癌症进展途径中，正在探索以开发可能适用于男性的疗法 癌症。由于在VA治疗的患者中有11％是癌症存活，因此我们的研究具有重要的影响 在改善VA的医疗保健方面。 实验室的其他研究是关于1）与乳腺癌转移相关的机制 和治疗性抗性； 2）正常乳腺生物学中的遗传血统依赖性变异； 3）定义 使用单细胞基因组学的乳腺癌细胞细胞细胞，4）暴露于外生理氧气的影响 在正常和癌症干细胞上； 5）通过了解最早的理解化学预防策略 乳腺癌计划中的事件。这些研究与VA资助的研究没有重叠，并由 独立机构。这些持续努力的目标是全面了解乳腺癌 发展和发展，并进一步有助于个性化乳腺癌的特征和 治疗。我们旨在开发基于细胞的细胞和探索疗法对乳腺癌进行分类的方法 基于基因组畸变的方式。我们关于外生物学氧作用的研究有望 更改组织收集的方法进行生物标志物发现。实验室已经非常有生产力 自2015年以来，有29份出版物的年份包括著名期刊上的两份共同作者出版物 自然与自然传播以及癌症等期刊上的几位高级作者出版物 研究。我们的出版物已获得15,100多种引用，H因子为62。 IU和VA的基础设施以及机构内部和外部的合作以及继续 在过去的23年中，校外资金使我们能够实现这些目标。 除研究外，我还参与了心理初级教师，博士后研究员，毕业生 过去23 年（> 50 Menees）。我在国家和国际一级的各个赠款审查委员会任职/任职 作为著名期刊（例如癌症研究）的编辑。自2015年以来，我邀请了37个 国家和国际场所的讲座强调了我们研究的重要性和认可。