Diversity Supplement to R01 Parent Grant CA186885

R01 家长补助金 CA186885 的多样性补充

• 批准号: 9251089
• 负责人: Hidayatullah G. Munshi
• 金额: $ 12.87万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251089
• 关键词: Acetylation; Adenocarcinoma Cell; Affect; Area; Attenuated; Biological Models; Bromodomain; Characteristics; Chromatin Structure; Clinical Trials; Collagen; Complex; Coupled; DNA Damage; Data; Development; Effectiveness; Epigenetic Process; Exhibits; Fibrosis; Future; Goals; Gold; Growth; Health; Histone Acetylation; Histone H3; Human; In Vitro; KRAS2 gene; Lead; Literature; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Minor; Mission; Modeling; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patient-Focused Outcomes; Production; Protein Family; Protein Inhibition; Proteins; Public Health; Reader; Regulation; Reporting; Research; Research Support; Resistance; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Tertiary Protein Structure; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; United States National Institutes of Health; Work; attenuation; base; cancer stem cell; chemotherapy; evidence base; expectation; gemcitabine; histone acetyltransferase; human disease; improved; in vivo; inhibitor/antagonist; innovation; mouse model; mutant; nanoparticle; novel; nucleoside analog; overexpression; parent grant; protein function; public health relevance; response; stellate cell; stem cell population; targeted treatment; tumor; tumor growth

DESCRIPTION (provided by applicant): The bromodomain (BRD) and extra terminal domain (BET) family of proteins, which function as 'readers' of histone acetylation marks, mediate growth of pancreatic ductal adenocarcinoma (PDAC) cells in 3D collagen. Additionally, PDAC cells in 3D collagen demonstrate chemoresistance through increased expression of high mobility group A2 (HMGA2), an architectural protein that regulates chromatin structure. The long-term goal is to help develop novel mechanism-based targeted therapies for the treatment of PDAC. The objective in this application is to determine how BET proteins mediate chemoresistance and contribute to fibrosis in vivo. The central hypothesis is that BET protein inhibition will decrease PDAC tumor growth and increase chemosensitivity by decreasing the cancer stem cell population and HMGA2 protein function, respectively. A second hypothesis is that BET inhibition will lead to an attenuation of fibrosis in PDAC tumors. These hypotheses are based on strong preliminary data demonstrating that BET inhibitors decrease growth of PDAC and stellate cells in 3D collagen. In addition, treatment of PDAC cells with BET inhibitors decreases cancer stem cell population and represses HMGA2. The rationale is that a determination of the role and underlying mechanism of BET proteins in PDAC progression in vivo is likely to contribute substantively to a conceptual framework whereby new clinically effective targeted therapies can ultimately be developed. Three specific aims are proposed: 1) Determine the role of BET proteins in PDAC progression in vivo; 2) Evaluate the ability of BET protein inhibition to increase chemotherapy sensitivity; and 3) Evaluate the ability of BET protein inhibition to attenuate fibrosis. Under the first aim, the effect of BET inhibitors on PDAC progression will be determined in mouse models. Further, the extent to which BET inhibitors decrease PDAC stem cell population in vivo will be evaluated. Also, the ability of gold nanoparticles (Au-NPs) coupled with BRD4 siRNA to inhibit tumor growth will be determined. For the second aim, the ability of BET inhibitors to increase chemotherapy efficacy will be evaluated in 3D collagen and in mouse models. Additionally, the role of BET proteins in DNA damage response and the contribution of HMGA2 to BET protein regulation of chemoresistance will be assessed. In the third aim, the mechanism by which BET inhibitors regulate stellate cell activation and collagen production will be determined. The effectiveness of BET inhibitors and Au-NPs functionalized with BRD4 siRNA to attenuate fibrosis in mouse models will also be evaluated. The research proposed is innovative because it utilizes complex models of pancreatic cancer, including in vitro organotypic cultures and in vivo orthotopic and transgenic mouse models to determine the role of BET proteins in PDAC progression. An additional innovation is the use of Au-NPs functionalized with siRNAs to downregulate BRD4 expression in the model systems. This proposed research is significant because it is expected to provide strong scientific justification for the continued development and future clinical trials of BET inhibitors in PDAC.

描述（由申请人提供）：溴结构域 (BRD) 和额外末端结构域 (BET) 蛋白家族充当组蛋白乙酰化标记的“读取器”，介导 3D 胶原中胰腺导管腺癌细胞 (PDAC) 的生长。此外，3D 胶原蛋白中的 PDAC 细胞通过增加高迁移率基团 A2 (HMGA2)（一种调节染色质结构的结构蛋白）的表达来表现出化疗耐药性。长期目标是帮助开发新的基于机制的靶向疗法来治疗 PDAC。本应用的目的是确定 BET 蛋白如何介导化疗耐药性并促进体内纤维化。中心假设是，BET 蛋白抑制将分别通过减少癌症干细胞群和 HMGA2 蛋白功能来减少 PDAC 肿瘤生长并增加化疗敏感性。第二个假设是 BET 抑制将导致 PDAC 肿瘤纤维化减弱。这些假设基于强有力的初步数据，表明 BET 抑制剂可减少 3D 胶原蛋白中 PDAC 和星状细胞的生长。此外，用 BET 抑制剂处理 PDAC 细胞会减少癌症干细胞数量并抑制 HMGA2。其基本原理是，确定 BET 蛋白在体内 PDAC 进展中的作用和潜在机制可能会对概念框架做出实质性贡献，从而最终开发出新的临床有效的靶向疗法。提出了三个具体目标：1）确定 BET 蛋白在体内 PDAC 进展中的作用； 2）评价BET蛋白抑制提高化疗敏感性的能力； 3) 评估BET蛋白的能力 抑制作用以减轻纤维化。第一个目标是在小鼠模型中确定 BET 抑制剂对 PDAC 进展的影响。此外，还将评估 BET 抑制剂减少体内 PDAC 干细胞群的程度。此外，还将确定金纳米颗粒 (Au-NP) 与 BRD4 siRNA 结合抑制肿瘤生长的能力。对于第二个目标，将在 3D 胶原蛋白和小鼠模型中评估 BET 抑制剂提高化疗疗效的能力。此外，还将评估 BET 蛋白在 DNA 损伤反应中的作用以及 HMGA2 对 BET 蛋白化疗耐药性调节的贡献。第三个目标是确定 BET 抑制剂调节星状细胞活化和胶原蛋白产生的机制。还将评估 BET 抑制剂和 BRD4 siRNA 功能化的 Au-NP 减轻小鼠模型纤维化的有效性。这项研究具有创新性，因为它利用复杂的胰腺癌模型，包括体外器官型培养物以及体内原位和转基因小鼠模型来确定 BET 蛋白在 PDAC 进展中的作用。另一项创新是使用带有 siRNA 功能的 Au-NP 来下调模型系统中的 BRD4 表达。这项拟议的研究意义重大，因为它有望为 PDAC 中 BET 抑制剂的持续开发和未来临床试验提供强有力的科学依据。