BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10702086
• 负责人: Vijayasaradhi Setaluri
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702086
• 关键词: Agreement; Aircraft; American; Area; Arthritis; Award; Biological Markers; Biomedical Engineering; Biosensor; Biotechnology; Blood; Book Chapters; Cell Line; Cell surface; Cells; Cellular biology; Clinical; Collaborations; Complex; Congresses; Connective Tissue; Country; Cutaneous Melanoma; Cyclic AMP; Data; Dependence; Dermal; Dermatology; Detection; Development; Devices; Diagnosis; Disease; Disseminated Malignant Neoplasm; Early Diagnosis; Early treatment; Engineering; Environmental Risk Factor; Etiology; Exercise; Exposure to; Faculty; Fibroblasts; Funding; Funding Agency; General Population; Goals; Grant Review; Growth; Heterogeneity; Hour; Human; Immunotherapy; Incidence; Industry; International; Investigation; Journals; Knowledge; Lab On A Chip; Laboratories; Leadership; Legal patent; Licensing; Malignant Neoplasms; Mediating; Medical Research; Medical Surveillance; Medicine; Melanoma Cell; Mentors; Metabolic; Metastatic Melanoma; Methods; Microfluidic Microchips; Microfluidics; Military Personnel; Modeling; Molecular; Monitor; Neoplasm Circulating Cells; Neoplasm Metastasis; Occupations; Paraffin Embedding; Patient Monitoring; Patients; Peer Review; Phenotype; Pigments; Positioning Attribute; Postdoctoral Fellow; Prevention; Prognostic Marker; Prospective Studies; Proteins; Recording of previous events; Reporting; Research; Research Personnel; Research Project Grants; Residual Neoplasm; Risk; Role; Scientist; Sea; Signal Transduction; Skin; Skin Cancer; Societies; Solar Energy; Staging; Study Section; Surface; Training; Translating; Translational Research; Tumor Cell Biology; Tumor Tissue; Tumor-Derived; UV Radiation Exposure; Ultraviolet Rays; United States National Academy of Sciences; United States National Institutes of Health; Universities; Veterans; Wing; active duty; anticancer research; cancer diagnosis; cancer therapy; career; chemotherapy; combat; editorial; experience; improved; in vitro Model; indexing; keratinocyte; liquid biopsy; macromolecule; melanoma; melanomagenesis; member; microfluidic technology; mortality; mouse model; novel; operation; patient biomarkers; peripheral blood; phenotypic biomarker; prevent; programs; prospective; response; restoration; service member; therapy resistant; trend; tumor; tumor growth; tumor progression; undergraduate student

Ongoing research in my laboratory is focused on three broad areas: 1) understanding the molecular mechanisms that drive melanoma tumor development and progression, 2) defining the role of skin microenvironment on melanomagenesis, and 3) identifying prognostic biomarkers for patients diagnosed with early-stage melanoma. The goal of the research project #1, which is funded by VA BLR&D Merit Review Award, is to understand the role of EPACs, proteins that mediate the alternative cAMP signaling, in promoting the growth of primary melanoma and the mechanism involved in metabolic adaptation that abolishes EPAC dependency during tumor progression. We are exploring inhibition of EPAC signaling in primary melanoma and restoration of EPAC dependency in metastatic melanoma as strategies, respectively, for prevention and treatment of melanoma in Veterans as well as general population. In project #2, we are modeling melanomagenesis using human skin-on-a-chip. The rationale for this project is that while genetically modified mouse models and human melanoma cell lines models in vitro are useful, they do not fully mimic the complex interactions that occur during melanomagenesis in the intact human skin microenvironment. The goal of the DoD Peer Reviewed Medical Research Program-funded research is to understand the role of epidermal keratinocytes and dermal fibroblasts in melanomagenesis to devise strategies for melanoma prevention in active service members and Veterans with increased risk of melanoma. These research projects with in-depth focus on cell and molecular aspects of melanoma also involve translational research using retrospective analysis of fixed and paraffin embedded human primary melanoma tumor tissues. The major focus of my future research is to translate our findings in prospective investigations in Veterans diagnosed with early-stage cutaneous melanoma. Recently, a collaboration with Drs. Gunasekaran and Jose Ayuso, biomedical engineers with expertise in biosensors and microfluidic technology, respectively, allowed us to develop a sensitive biosensor that we propose to employ for prospective studies targeted to detection of circulating melanoma cells in Veteran diagnosed with early-stage melanoma. In proof-of-principle studies, we showed selective and sensitive detection of cells in patient blood. We show that this immunosensor is readily adaptable, in an arrayed format, for simultaneous detection of multiple biomarkers and can be incorporated into a microfluidic device and multiplexed to identify and capture subsets of CTC based on their cell surface markers for phenotypic and molecular characterization. The goal of project #3 is to identify and characterize circulating tumor cells (CTC) in the peripheral blood as indicators of risk of metastatic melanoma and residual disease. The proposed specific aims of this project are a) detection and capture of melanoma cells based on surface marker heterogeneity, b) detection and characterization of CTC heterogeneity using multiplexed microfluidic immuno-sensor array and c) phenotypic and molecular characterization of CTC. These studies will be supported by VA CSR&D Merit Review Award application selected for funding. During the Research Career Scientist Award period, I plan to integrate our understanding of molecular mechanisms in melanoma progression with prospective studies that often require long-term monitoring of the patients. I plan to leverage the microfluidic platform to develop human skin-on-chip to investigate the relationship between environmental factors and risk of melanoma in Veterans. More importantly, the Research Career Scientist Award support will allow us to collect the critical additional data to support my next round of Merit Review application by going beyond detection of circulating melanoma cells to leverage the liquid biopsy for monitoring risk of metastatic melanoma in Veterans.

我的实验室正在进行的研究集中在三个广泛的领域：1）了解分子 驱动黑色素瘤肿瘤发育和进展的机制，2）定义皮肤的作用 在黑色素作用上的微环境和3）鉴定被诊断为患有患者的患者的预后生物标志物 早期黑色素瘤。研究项目＃1的目标，该项目由VA Blr＆d优异评论奖资助， 是要了解EPAC的作用，EPAC的作用，介导替代cAMP信号传导的蛋白质在促进生长中的作用 原发性黑色素瘤及其代谢适应的机制，以废除EPAC依赖性 在肿瘤进展过程中。我们正在探索对原发性黑色素瘤中EPAC信号传导的抑制和恢复 EPAC在转移性黑色素瘤中的依赖性分别作为预防和治疗的策略 退伍军人和普通人群的黑色素瘤。在项目2中，我们正在使用 片上的人皮。该项目的理由是，虽然基因修饰的小鼠模型和人类 体外黑色素瘤细胞系模型很有用，它们并未完全模仿在此期间发生的复杂相互作用 完整的人皮肤微环境中的黑色素作用。 DOD同行审查的医疗的目标 研究计划资助的研究是了解表皮角质形成细胞和皮肤成纤维细胞的作用 在黑色素作和在活跃的服务成员和退伍军人中预防黑色素瘤的策略中 黑色素瘤的风险增加。这些研究项目深入侧重于细胞和分子方面 黑色素瘤还使用固定和石蜡嵌入人的回顾性分析涉及转化研究 原发性黑色素瘤组织。我未来研究的主要重点是将我们的发现转化为潜在的 对被诊断为早期皮肤黑色素瘤的退伍军人进行的调查。 最近，与博士合作。 Gunasekaran和Jose Ayuso，具有专业知识的生物医学工程师 生物传感器和微流体技术分别使我们能够开发一种敏感的生物传感器，我们 建议用于用于检测老兵循环黑色素瘤细胞的前瞻性研究 被诊断为早期黑色素瘤。在原则研究中，我们显示了选择性和敏感检测 患者血液中的细胞。我们证明，这种免疫传感器很容易以阵列格式适应 同时检测多个生物标志物，可以合并到微流体设备中并多重 基于其表型和分子的细胞表面标记识别和捕获CTC的子集 表征。项目＃3的目的是识别和表征循环肿瘤细胞（CTC） 外围血作为转移性黑色素瘤和残留疾病风险的指标。提出的特定目的 该项目的是a）基于表面标记异质性的检测和捕获黑色素瘤细胞，b） 使用多路复用微流体传感器阵列和C的CTC异质性检测和表征 CTC的表型和分子表征。这些研究将得到VA CSR＆D的优点评论的支持 选择资金申请。 在研究职业科学家奖期间，我计划整合我们对分子的理解 黑色素瘤进展的机制通过前瞻性研究，通常需要长期监测 患者。我计划利用微流体平台开发片上的人皮肤来调查这种关系 在环境因素和退伍军人中黑色素瘤的风险之间。更重要的是，研究职业 科学家奖的支持将使我们能够收集关键的其他数据以支持我的下一轮功绩 通过超越循环黑色素瘤细胞的检测来审查应用，以利用液体活检 监测退伍军人转移性黑色素瘤的风险。