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主要集中在三个广泛的领域：1）了解分子 驱动黑色素瘤肿瘤发生和进展的机制，2) 定义皮肤的作用 黑色素瘤发生的微环境，以及 3) 确定诊断患有黑色素瘤的患者的预后生物标志物 早期黑色素瘤。由 VA BLR&D 优异评审奖资助的研究项目 #1 的目标， 是为了了解 EPAC（介导替代 cAMP 信号传导的蛋白质）在促进生长中的作用 原发性黑色素瘤的发病机制以及消除 EPAC 依赖性的代谢适应机制 在肿瘤进展期间。我们正在探索抑制原发性黑色素瘤中的 EPAC 信号传导并恢复 转移性黑色素瘤中的 EPAC 依赖性分别作为预防和治疗的策略 退伍军人和普通人群中的黑色素瘤。在项目 #2 中，我们使用以下方法模拟黑色素瘤发生 人类皮肤芯片。该项目的基本原理是，虽然转基因小鼠模型和人类 体外黑色素瘤细胞系模型是有用的，它们不能完全模拟在黑色素瘤细胞系中发生的复杂相互作用。 完整的人类皮肤微环境中的黑色素瘤发生。国防部同行评审医学的目标 研究计划资助的研究旨在了解表皮角质形成细胞和真皮成纤维细胞的作用 在黑色素瘤发生中制定现役军人和退伍军人黑色素瘤预防策略 黑色素瘤的风险增加。这些研究项目深入关注细胞和分子方面 黑色素瘤还涉及利用固定和石蜡包埋的人类的回顾性分析进行转化研究 原发性黑色素瘤肿瘤组织。我未来研究的主要重点是将我们的发现转化为前瞻性的 对诊断患有早期皮肤黑色素瘤的退伍军人进行的调查。 最近，与 Drs 的合作。 Gunasekaran 和 Jose Ayuso，生物医学工程师，拥有以下专业知识 生物传感器和微流体技术分别使我们能够开发出一种敏感的生物传感器 提议用于旨在检测退伍军人中循环黑色素瘤细胞的前瞻性研究 被诊断患有早期黑色素瘤。在原理验证研究中，我们展示了选择性和灵敏的检测 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形式适应 同时检测多种生物标志物，可以合并到微流体装置中并进行多重检测 根据表型和分子的细胞表面标记来识别和捕获 CTC 子集 表征。项目 #3 的目标是识别和表征循环肿瘤细胞 (CTC) 外周血作为转移性黑色素瘤和残留病风险的指标。拟议的具体目标 该项目的主要内容是 a) 基于表面标记异质性检测和捕获黑色素瘤细胞，b) 使用多重微流控免疫传感器阵列检测和表征 CTC 异质性，以及 c) CTC 的表型和分子特征。这些研究将得到 VA CSR&D Merit Review 的支持 选定资助的奖励申请。 在研究职业科学家奖期间，我计划整合我们对分子的理解 通过前瞻性研究来了解黑色素瘤进展的机制，这些研究通常需要长期监测 患者。我计划利用微流控平台开发人体皮肤芯片来研究两者之间的关系 环境因素与退伍军人黑色素瘤风险之间的关系。更重要的是，研究生涯 科学家奖的支持将使我们能够收集关键的额外数据来支持我的下一轮优异奖 通过超越检测循环黑色素瘤细胞来利用液体活检来审查应用程序 监测退伍军人转移性黑色素瘤的风险。