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Integrative Analysis of the Aging Peritoneum in Metastatic Receptivity

老化腹膜转移容受性的综合分析

基本信息

批准号：
10250399
负责人：
Elizabeth Harper
金额：
$ 4.6万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10250399
关键词：
Abdomen Adhesions Adipocytes Adipose tissue Affect Age Aging Allografting American Animals Antitumor Response Area Atomic Force Microscopy Biomechanics CD8B1 gene Cancer Patient Carcinomatosis Cell Transplantation Cells Cessation of life Chemicals Chronic Collagen Collagen Type I Complex Cytometry Cytotoxic T-Lymphocytes Data Development Diagnosis Differential Scanning Calorimetry Disease Disseminated Malignant Neoplasm Distant Doctor of Philosophy Ensure Environment Generations Goals Greater sac of peritoneum Home Immune Immune system Immunotherapy In Vitro Infection Infiltration Inflammation Integration Host Factors Invaded Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of abdomen Malignant neoplasm of ovary Mammalian Oviducts Measures Membrane Mesothelial Cell Metastatic to Microscopy Modification Mus Neoplasm Metastasis Omentum Organ Ovarian aging Ovary Patients Peritoneal Peritoneal Mesothelial Cell Peritoneum Phase Population Positioning Attribute Pre-Clinical Model Predisposition Primary Neoplasm Principal Investigator Prognosis Proliferating Proteome Regulation Regulatory T-Lymphocyte Research Research Personnel Research Project Grants Research Training Risk Factors Role Scanning Electron Microscopy Secondary Lesion Series Site Skin Structure Surface Survival Rate T-Lymphocyte Tissues Training Translational Research Transplantation Tumor Burden Tumor-infiltrating immune cells Visceral Woman age effect age related aged cancer cell cancer diagnosis career career development cohort crosslink experimental study fighting high risk immune function immunosenescence improved in vitro Assay in vivo intraperitoneal monolayer mortality risk multidisciplinary neoplastic cell older women pre-doctoral prognostic tool response second harmonic small molecule success tandem mass spectrometry trend tumor tumor immunology tumor microenvironment tumor progression

项目摘要

The overall goal of this proposal is to provide a comprehensive plan of research training and career development to enable the principal investigator to successfully complete her PhD and acquire a competitive postdoctoral position performing translational research in the fields of aging and cancer. Phase I focuses on completion of ongoing PhD training investigating the role of the aging microenvironment in ovarian cancer (OvCa) metastasis. OvCa is the most fatal gynecologic malignancy and the 5th leading cause of overall cancer death among American women with a low 5-year survival rate, as 75% of women are diagnosed with disseminated intra-peritoneal (IP) metastasis. OvCa metastasis differs from most other cancers in that cells detach from the primary tumor, shed into the peritoneal cavity, adhere to the peritoneal mesothelial cell (MC) monolayer, intercalate within this layer, and invade into the submesothelial matrix, where they proliferate and form secondary lesions. Aging is the biggest risk factor for the development of OvCa. Half of OvCa diagnoses are in women over the age of 63, and older OvCa patients have a higher risk of mortality. Despite this, age is understudied in the OvCa field. Even though the peritoneum has near the same surface area as the skin, the effect of age on the peritoneum has not been systematically evaluated. Using three distinct murine pre-clinical models of aging and OvCa metastasis, our lab previously demonstrated enhanced metastatic seeding of peritoneal structures in aged mice accompanied by altered immune cell infiltration. Current preliminary data in this application show that there are distinct differences observed when comparing peritoneal collagen ultrastructure in young and aged animals at major metastatic sites. Moreover, using purified collagen from young versus aged mice in a panel of in vitro assays, we showed increased invasion of OvCa cells through aged collagen relative to young, despite no difference in adhesion or proliferation. Differential susceptibility to proteolytic remodeling was also observed. This data supports our hypothesis that age-related changes to the metastatic environment enhance ovarian cancer metastasis in aged patients. The Phase I goal of the proposed research is to identify small molecules that can target these age-related structural modifications in collagen with the goal of reducing metastatic dissemination in aged mice. Additional studies will evaluate the other major component of the peritoneal cavity, the visceral adipocytes, with characterization of age-related changes in the adipocytes proteome. The Phase II goal will focus on the immune landscape of an aging cancer. Studies will focus on T cell infiltration and immunosenescence with aging. The emphasis on multi-disciplinary aspects of aging throughout the training, combining a predoctoral focus on the tumor metastatic microenvironment and a postdoctoral focus on the tumor immune system will position the candidate for a translational career investigating the role of aging on immunotherapy and mechanisms by which to improve immunotherapy responses in aged cancer patients.

该提案的总体目标是提供一个全面的研究培训和职业发展计划，使主要研究者能够成功完成博士学位，并获得一个有竞争力的博士后职位，在衰老和癌症领域进行转化研究。第一阶段的重点是完成正在进行的博士培训，研究衰老微环境在卵巢癌（OvCa）转移中的作用。OvCa是最致命的妇科恶性肿瘤，也是美国女性总体癌症死亡的第五大原因，5年生存率较低，因为75%的女性被诊断为弥漫性腹膜内（IP）转移。OvCa转移与大多数其他癌症的不同之处在于，细胞从原发性肿瘤分离，脱落到腹膜腔中，粘附到腹膜间皮细胞（MC）单层，插入该层内，并侵入间皮下基质，在那里它们增殖并形成继发性病变。衰老是OvCa发展的最大风险因素。OvCa诊断的一半是63岁以上的女性，年龄较大的OvCa患者死亡风险较高。尽管如此，年龄在OvCa领域研究不足。尽管腹膜与皮肤的表面积几乎相同，但年龄对腹膜的影响尚未得到系统评价。使用三种不同的衰老和OvCa转移的小鼠临床前模型，我们的实验室先前证明了老年小鼠腹膜结构的转移性种植增强，伴有免疫细胞浸润改变。本申请的当前初步数据显示，在主要转移部位比较年轻和老年动物的腹膜胶原超微结构时，观察到明显差异。此外，使用纯化的胶原蛋白从年轻与老年小鼠在一组体外试验中，我们发现增加的OvCa细胞的入侵，通过老年胶原蛋白相对于年轻的，尽管没有差异的粘附或增殖。还观察到对蛋白水解重塑的不同敏感性。这一数据支持我们的假设，即年龄相关的转移环境的变化增强了老年患者的卵巢癌转移。拟议研究的第一阶段目标是确定可以靶向胶原蛋白中这些与年龄相关的结构修饰的小分子，目的是减少老年小鼠的转移性播散。其他研究将评估腹腔的其他主要成分，内脏脂肪细胞，脂肪细胞蛋白质组中年龄相关变化的特征。第二阶段的目标将集中在衰老癌症的免疫景观。研究将集中在T细胞浸润和免疫衰老与衰老。在整个培训过程中强调衰老的多学科方面，结合对肿瘤转移微环境的博士前关注和对肿瘤免疫系统的博士后关注，将使候选人定位于翻译职业，研究衰老对免疫治疗的作用以及改善老年癌症患者免疫治疗反应的机制。