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(申请人提供)：溴域(BRD)和额外末端结构域(BET)家族的蛋白质，其功能是组蛋白乙酰化标记的‘阅读器’，在3D胶原蛋白中介导胰腺导管腺癌细胞(PDAC)的生长。此外，3D胶原中的PDAC细胞通过高迁移率组A2(HMGA2)的表达增加而表现出化疗耐药性，HMGA2是一种调节染色质结构的建筑蛋白。长期目标是帮助开发治疗PDAC的新的基于机制的靶向疗法。这项应用的目的是确定BET蛋白如何在体内介导化疗耐药和促进纤维化。中心假设是，抑制BET蛋白将分别通过减少肿瘤干细胞数量和HMGA2蛋白功能来减少PDAC肿瘤的生长和增加对化疗的敏感性。第二个假设是，抑制BET将导致PDAC肿瘤纤维化的减轻。这些假说建立在强有力的初步数据基础上，这些数据表明，BET抑制剂减少了3D胶原中PDAC和星状细胞的生长。此外，用BET抑制剂治疗PDAC细胞减少了癌症干细胞数量，并抑制了HMGA2。其基本原理是，对BET蛋白在体内PDAC进展中的作用和潜在机制的确定可能对最终开发新的临床有效的靶向治疗的概念框架做出实质性贡献。提出三个具体目标：1)确定BET蛋白在体内PDAC进展中的作用；2)评估抑制BET蛋白增加化疗敏感性的能力；以及3)评估BET蛋白的能力 抑制纤维化。在第一个目标下，将在小鼠模型中确定BET抑制剂对PDAC进展的影响。此外，将评估BET抑制剂在多大程度上减少体内的PDAC干细胞数量。此外，金纳米颗粒(Au-NPs)与BRD4 siRNA偶联抑制肿瘤生长的能力将被确定。对于第二个目标，BET抑制剂提高化疗疗效的能力将在3D胶原和小鼠模型中进行评估。此外，还将评估BET蛋白在DNA损伤反应中的作用以及HMGA2在BET蛋白调节化疗耐药中的作用。在第三个目标中，将确定BET抑制剂调节星状细胞激活和胶原产生的机制。BET抑制剂和BRD4 siRNA功能化的Au-NPs在减轻小鼠模型纤维化方面的有效性也将得到评估。这项研究具有创新性，因为它利用了复杂的胰腺癌模型，包括体外器官培养和体内原位和转基因小鼠模型，以确定BET蛋白在PDAC进展中的作用。另一项创新是使用带有siRNAs功能化的Au-NPs来下调模型系统中BRD4的表达。这项拟议的研究具有重要意义，因为它有望为BET抑制剂在PDAC中的继续开发和未来的临床试验提供强有力的科学依据。