HAPLN1 mediates collagen remodeling during aging to influence melanoma and immune cell motility

HAPLN1 在衰老过程中介导胶原蛋白重塑，从而影响黑色素瘤和免疫细胞运动

• 批准号: 9768146
• 负责人: Amanpreet Kaur
• 金额: $ 7.08万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768146
• 关键词: 3-Dimensional; Affect; Age; Age Factors; Aging; Architecture; Artificial skin; Automobile Driving; Award; Cells; Clinical; Collaborations; Collagen; Collagen Fiber; Collection; Data; Dermal; Disease; Elderly; Extracellular Matrix; Extracellular Matrix Proteins; Fiber; Fibroblasts; Fox Chase Cancer Center; Funding; Goals; Image; Imaging Techniques; Immune; Individual; Infiltration; Lead; Learning; Lymphocyte; MMP14 gene; Matrix Metalloproteinases; Measures; Mechanics; Mediating; Melanoma Cell; Mentors; Methods; Molecular; Morphology; Movement; Mus; Nature; Neoplasm Metastasis; Patients; Phase; Phenotype; Postdoctoral Fellow; Process; Production; Protein-Lysine 6-Oxidase; Proteins; Research; Research Proposals; Resistance; Resources; Role; Science; Signal Transduction; Skin; Skin Cancer; Structural Protein; Structure; T-Lymphocyte; TIMP3 gene; Techniques; Testing; The Wistar Institute; Training; Tumor-infiltrating immune cells; Universities; Work; age related; aged; anticancer research; base; career; career development; cell motility; cell type; crosslink; density; differential expression; immune resistance; improved; interstitial; keratinocyte; loss of function; melanocyte; melanoma; migration; negative affect; neoplastic cell; older patient; post-doctoral training; pre-doctoral; protein crosslink; protein structure; targeted treatment; tumor; tumor microenvironment; tumor progression

The increased aggressiveness of melanoma in elderly patients leads to increased metastasis and therapy resistance in these patients. Our goal in this proposed research is to understand the molecular mechanisms underlying age-­related increases in melanoma metastasis, as well as effects on the immune microenvironment. Our overall hypothesis is that aged patients have changes in the extracellular matrix (ECM) of the skin that leads to differential motility of melanoma and the immune cells in the tumor. To test this hypothesis, we will undertake two specific aims that are outlined in the research proposal. The proposed studies are based on my findings from my previous studies that aging affects the metastasis in melanoma cells. My work identified various proteins that are de-­regulated during aging, and our data showed a 35-­fold decrease in levels of a collagen crosslinking protein, HAPLN1, during aging. Firstly, we will assess the effect of collagen crosslinking mediated by HAPLN1 on mediating the changes in migration of melanoma cells from the tumor. Secondly, we will focus on changes in the infiltration of lymphocytes into the tumor when age-­related changes in HAPLN1 levels restructure the tumor ECM. We expect this research to generate targets for therapeutic implications in elderly melanoma patients. Apart from these goals, this NCI Predoctoral to Postdoctoral Fellow Transition Award will allow me to develop expertise in cancer research while providing me with funding to support my postdoctoral training. My training plan outlined in this proposal will take advantage of the extensive resources available to me at The Wistar Institute and University of the Sciences in the F99 phase of my training. During this phase, my training will be overseen by my mentor, Dr. Ashani Weeraratna who has successfully mentored several postdoctoral and clinical fellows in their academic careers.

古老患者黑色素瘤的侵略性提高导致转移和 这些患者的治疗耐药性。我们在这项拟议的研究中的目标是了解分子 与年龄相关的机制在黑色素瘤转移中增加，以及对 免疫微环境。我们的总体假设是老年患者的变化 皮肤的细胞外基质（ECM）导致黑色素瘤和免疫的差异运动 肿瘤中的细胞。 为了检验这一假设，我们将实现研究建议中概述的两个具体目标。 拟议的研究是基于我以前研究的发现，即衰老会影响 黑色素瘤细胞中的转移。我的工作确定了在衰老期间被脱离的各种蛋白质 而且我们的数据显示，胶原蛋白交联蛋白Hapln1的水平下降了35倍。 老化。首先，我们将评估通过Hapln1介导的胶原蛋白交联的影响 黑色素瘤细胞从肿瘤迁移的变化。其次，我们将重点介绍 当年龄相关的HAPLN1水平恢复时，淋巴细胞浸润到肿瘤中 肿瘤ECM。我们预计这项研究将产生对较早的热含义的目标 黑色素瘤患者。 除了这些目标外，NCI占主导地位及博士后过渡奖将使我能够 在癌症研究方面发展专业知识，同时为我提供资金来支持我的博士后 训练。我在此提案中概述的培训计划将利用大量资源 在我的培训的F99阶段，在Wistar Institute和Sciences大学可供我使用。 在此阶段，我的培训将由我的心理Ashani Weeraratna博士监督 成功地提到了学术职业的几个博士后和临床研究员。