Neural Mechanisms Driving Comorbid Parkinson's and Melanoma

驱动帕金森病和黑色素瘤共病的神经机制

• 批准号: 10668220
• 负责人: Pamela Del Valle
• 金额: $ 4.77万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668220
• 关键词: Allografting; Animals; Automobile Driving; Axon; Breast Adenocarcinoma; Data; Development; Environment; Exhibits; Genetic; Growth; Implant; In Situ; Infiltration; Knock-in; Knock-in Mouse; LRRK2 gene; Macrophage; Malignant Neoplasms; Mediating; Modeling; Mus; Mutation; Neoplasm Metastasis; Neurons; Outcome; Parkinson Disease; Patients; Pattern; Persons; Phosphotransferases; Population; Research; Risk; Series; Stress; Sympathetic Nervous System; Testing; Vascularization; Wild Type Mouse; Work; angiogenesis; behavioral response; comorbidity; epidemiology study; experimental study; genetic manipulation; high risk; in vivo; kinase inhibitor; melanoma; nerve supply; neural; neurogenesis; neuromechanism; pharmacologic; quantitative imaging; response; screening; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions

Project Summary/Abstract A series of epidemiological studies have shown that people with Parkinson’s disease (PD) have a significantly higher risk of developing melanoma and vice-versa. However, research on this comorbidity is sparse. One possible point of convergence lies in the sympathetic nervous system (SNS). Studies have shown that activating sympathetic axons residing in breast adenocarcinomas increases cancer growth and metastasis. Extending this, our preliminary data suggest that mice implanted with melanoma allografts and carrying a knock-in form of the LRRK2-G2019S mutation, the most common genetic contributor to PD, have enriched populations of sympathetic axons in their tumor microenvironment. Therefore, I hypothesize that a PD environment produces an altered melanoma response by regulating the activity and innervation of sympathetic axons in the tumor microenvironment. To investigate this, I am first characterizing melanoma progression and its neural microenvironment in WT and LRRK2-G2019S-knock in (GSKI) mice. The data show that the extent and pattern of melanoma growth is altered significantly in GSKI mice and that immunolabeled tumors show altered patterns of innervation, macrophage infiltration and angiogenesis. These and additional data will be used to establish the conditions and timing for testing whether LRRK2-G2019S-mediated alterations in melanoma growth lie downstream of local sympathetic axonal activity and to ascertain whether positive results can be reversed by inhibition of LRRK2 kinase activity, which is significantly elevated with the G2019S mutation. Studying the downstream effects of sympathetic axonal activity and innervation in a tumor microenvironment will create a fuller understanding of the neural mechanisms connecting PD and melanoma.

项目概要/摘要 一系列流行病学研究表明，患有帕金森病（PD）的人有显着的 患黑色素瘤的风险较高，反之亦然。然而，对这种合并症的研究很少。 可能的汇聚点在于交感神经系统（SNS）的激活。 乳腺癌中的交感神经轴突会增加癌症的生长和转移。 我们的初步数据表明，植入黑色素瘤同种异体移植物并携带敲入形式的小鼠 LRRK2-G2019S 突变是 PD 最常见的遗传因素，丰富了 肿瘤微环境中的交感神经轴突。 通过调节交感神经轴突的活动和神经支配来改变黑色素瘤反应 为了研究这一点，我首先描述了黑色素瘤的进展及其进展。 WT 和 LRRK2-G2019S-knock (GSKI) 小鼠中的神经微环境的数据显示程度和。 GSKI 小鼠中黑色素瘤的生长模式显着改变，免疫标记的肿瘤显示 这些和其他数据将用于神经支配、巨噬细胞浸润和血管生成的模式。 建立测试 LRRK2-G2019S 是否介导黑色素瘤生长改变的条件和时间 位于局部交感神经轴突活动的下游，并确定阳性结果是否可以通过以下方式逆转： 抑制 LRRK2 激酶活性，该活性随着 G2019S 突变而显着升高。 肿瘤微环境中交感神经轴突活动和神经支配的下游效应将产生 更全面地了解帕金森病和黑色素瘤之间的神经机制。