RESEARCH AND MENTORING EXCELLENCE IN DIVERSE AND INCLUSIVE ENVIRONMENT

多元化和包容性环境中的卓越研究和指导

• 批准号: 10606046
• 负责人: Aime T Franco
• 金额: $ 31.55万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-31 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10606046
• 关键词: Affect; Award; Benign; Cells; Data; Development; Disease; Distant; Endocrine; Environment; Event; Extracellular Matrix; Follicular thyroid carcinoma; Genetic; Incidence; Lead; MAP Kinase Gene; MAPK Signaling Pathway Pathway; Malignant Neoplasms; Malignant neoplasm of thyroid; Mentors; Modeling; Modification; Molecular; Mutation; Neoplasm Metastasis; Oncogene Activation; Oncogenic; Outcome; Papillary thyroid carcinoma; Pathologic; Pathway interactions; Prevention strategy; Proteins; Research; Signal Pathway; Signal Transduction; Site; Solid Neoplasm; Therapeutic; Thyroid Diseases; adenoma; clinical practice; mouse model; new therapeutic target; novel therapeutics; recruit; tumor; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Thyroid cancer is the most common endocrine malignancy and incidences are rising. Thyroid cancers of follicular cell origin stand out among solid tumors because many of the tumor -initiating genetic events are known. Activating mutations of effectors of the MAPK signaling pathway are associated with both follicular and papillary thyroid cancer, and occur throughout the spectrum of thyroid diseases from benign adenomas through therapeutically refractive poorly-differentiated disease. Despite sharing activation of the MAPK pathway, activation via different effectors in the pathway results in distinct and unique pathological outcomes, including metastasis to distinct distant sites. We do not understand how activation of a single pathway via different mutations within the signaling cascade results in different pathological outcomes and recruitment of different tumor microenvironments. This paradigm is seen not only in thyroid cancer, but in other malignancies. We will utilize recently generated mouse models of thyroid cancer to model follicular and papillary thyroid cancers to study how activation of the oncogene Hras versus Braf affects tumor development and can modify the tumor microenvironment. We hypothesize that mode of activation contributes to stromal recruitment and extracellular matrix (ECM) modification, thus contributing to the pathobiology of tumor formation and progression. The data generated in these studies will provide a better understanding of the mechanisms by which different oncogenic events that activate the same pathway predisposes the development distinct pathological outcomes. We hope to use these data to develop novel therapeutic and prevention strategies for thyroid cancer.

项目总结/摘要 甲状腺癌是最常见的内分泌恶性肿瘤，发病率正在上升。甲状腺癌 滤泡细胞起源在实体瘤中很突出，因为许多肿瘤起始的遗传事件 知道的MAPK信号通路效应子的激活突变与滤泡和淋巴结转移有关。 乳头状甲状腺癌，发生在整个甲状腺疾病的良性腺瘤 通过治疗屈光性分化不良的疾病。尽管有MAPK的共同激活， 在该通路中，经由通路中不同效应物的激活导致不同且独特的病理结果， 包括转移到不同的远处部位。我们不知道如何激活一个单一的途径，通过 信号级联中的不同突变导致不同的病理结果， 不同的肿瘤微环境这种模式不仅见于甲状腺癌，也见于其他癌症。 恶性肿瘤。我们将利用最近产生的甲状腺癌小鼠模型来模拟滤泡癌和甲状腺癌。 甲状腺乳头状癌，研究癌基因Hras与Braf的激活如何影响肿瘤的发展 并且可以改变肿瘤微环境。我们假设，激活模式有助于基质 募集和细胞外基质（ECM）修饰，从而有助于肿瘤的病理生物学 形成和发展。这些研究产生的数据将使人们更好地了解 不同的致癌事件激活相同的通路， 发展不同的病理结果。我们希望利用这些数据开发新的治疗方法， 甲状腺癌的预防策略。