Integrative Analysis of the Aging Peritoneum in Metastatic Receptivity

老化腹膜转移容受性的综合分析

• 批准号: 10734101
• 负责人: Elizabeth Harper
• 金额: $ 7.12万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734101
• 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; Elasticity; 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; Microscopy; Modification; Mus; Neoplasm Metastasis; Omentum; Organ; Ovarian aging; Ovary; Patients; Peritoneal; Peritoneal Mesothelial Cell; Peritoneum; Phase; Population; Positioning Attribute; Postdoctoral Fellow; 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 cell infiltration; T-Lymphocyte; Tissues; Traction; 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 cell infiltrate; immune function; immunosenescence; improved; in vitro Assay; in vivo; intercalation; 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

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项全面的研究培训和职业发展计划，以使首席研究人员能够成功完成博士学位，并获得在衰老和癌症领域进行转化研究的有竞争的博士后职位。第一阶段的重点是完成正在进行的博士学位培训，研究了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5年生存率较低的美国女性总体癌症死亡的第五个主要原因，因为有75％的妇女被诊断出患有腹腔内（IP）转移。 OVCA转移与大多数其他癌症不同，因为细胞从原发性肿瘤中脱离，脱落到腹膜腔中，粘附在腹膜间皮细胞（MC）单层，在该层中插入，并入侵进入子宫内膜，并在其中扩散并形成次要的次要次要。衰老是OVCA发展的最大危险因素。 OVCA诊断的一半是在63岁以上的女性中，而老年OVCA患者的死亡风险更高。尽管如此，OVCA领域仍在研究年龄。即使腹膜与皮肤的表面积接近相同的表面积，但尚未系统地评估年龄对腹膜的影响。使用三种不同的鼠临床前衰老和OVCA转移模型，我们的实验室先前证明了衰老小鼠的腹膜结构的转移性增强，并伴随着免疫细胞浸润的改变。本应用程序中的当前初步数据表明，在比较主要转移性部位的年轻动物和老年动物的腹膜胶原蛋白超微结构时，观察到明显的差异。此外，在体外测定面板中，使用来自年轻小鼠的纯化胶原蛋白，尽管在粘附或增殖方面没有差异，但我们通过老化的胶原蛋白与年轻的胶原蛋白相对于年轻的胶原蛋白显示出增加的OVCA细胞的侵袭。还观察到了对蛋白水解重塑的差异敏感性。该数据支持我们的假设，即与年龄相关的转移环境变化可增强老年患者的卵巢癌转移。拟议的研究的第一阶段目标是鉴定可以针对胶原蛋白年龄相关的结构修饰的小分子，以减少老年小鼠的转移性传播。其他研究将评估腹膜腔的其他主要成分，即内脏脂肪细胞，并表征脂肪细胞蛋白质组与年龄相关的变化。 II期目标将集中于衰老癌症的免疫景观。研究将集中于随着衰老的T细胞浸润和免疫衰老。在整个培训中，重点介绍了衰老的多学科方面，将重点关注肿瘤转移性微环境和对肿瘤免疫系统的博士后关注将使候选者定位转化职业，以调查衰老对免疫治疗和机制的作用，从而改善免疫治疗疗法的反应症患者。