BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10618238
• 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/10618238
• 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; Classification; 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; Licensing; 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; PIK3CG gene; Pancreas; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Postdoctoral Fellow; Prevention strategy; Process; Productivity; 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; Seminal; Sex Differences; Signal Pathway; Skeletal Muscle; Socioeconomic Factors; Systemic disease; Techniques; Technology; Testing; Therapeutic; Tissue Banks; Tissues; Toremifene; Veterans; Woman; Work; anticancer research; biomarker discovery; bone; breast cancer progression; cancer cell; cancer initiation; cancer stem cell; cancer type; carcinogenesis; career; chemotherapy; editorial; effective therapy; epithelial to mesenchymal transition; estrogenic; experience; female sex hormone; genomic aberrations; genomic data; graduate student; health disparity; high risk; hormone therapy; 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.

项目概要： 我目前的研究重点是了解乳腺癌的发生机制和 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，但我们正在取得进展。 将乳腺癌评估为影响多个器官功能的全身性疾病。 相关死亡不仅仅是由于癌细胞转移到远处器官或对治疗产生耐药性 但也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恶病质的临床表现，身体 大多数乳腺癌患者的外观仍然“正常”，但骨骼肌质量却没有减少。 明显的体重减轻是很常见的，这种肌肉质量的损失与我们的不良结果有关。 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，开发 骨骼肌变化的生物标志物，用于早期检测癌症引起的全身效应和治疗 限制癌症对骨骼肌影响的方法这些研究已扩展到其他癌症。 我们观察到了膀胱癌、肺癌、胰腺癌和头颈癌的特定分子差异。 因此，患有相同类型癌症的男性和女性的骨骼肌存在性别差异。 正在探索癌症进展途径，以开发可能适用于男性的疗法 由于 VA 接受治疗的患者中有 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。 实验室的其他研究涉及 1) 与乳腺癌转移相关的机制 和治疗耐药性；2) 正常乳腺生物学的遗传祖先依赖性变异； 使用单细胞基因组学研究乳腺癌的细胞起源，4) 暴露于生理外氧气的影响 正常和癌症干细胞；5) 通过尽早了解来制定化学预防策略 这些研究与 VA 资助的研究没有重叠。 这些持续努力的目标是全面了解乳腺癌。 的发展和进展，并进一步有助于个体化乳腺癌特征和 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。 我们对生理外氧气影响的研究预计将基于基因组畸变。 改变生物标志物发现的组织收集方法 实验室一直非常富有成效。 自 2015 年以来已发表 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 Nature 和 Nature Communications 以及在 Cancer 等期刊上发表的多篇资深作者论文 研究。我们的出版物已被引用超过 15,100 次，H 因子为 62。 印第安纳大学和弗吉尼亚州的基础设施，以及机构内外的合作和持续的 过去 23 年的外部资金使我们能够实现这些目标。 除了研究之外，我还参与指导初级教师、博士后研究员、研究生 学生、医学生、高中生和高中教师过去 23 年的暑期研究 年（超过 50 名受训者），我曾在国家和国际各级的各种资助审查委员会任职 自2015年起担任Cancer Research等知名期刊的编辑，已受邀37次。 在国内和国际场所的讲座强调了我们研究的重要性和认可。