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.

项目摘要/摘要 一系列流行病学研究表明，患有帕金森氏病（PD）的人有明显的 较高的黑色素瘤风险和反之亦然。但是，对这种合并症的研究很少。一 收敛的可能点在于交感神经系统（SNS）。研究表明，激活 居住在乳腺癌中的交感神经轴突会增加癌症的生长和转移。扩展这一点， 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击形式的小鼠 LRRK2-G2019S突变是PD的最常见遗传贡献者，具有丰富的种群 肿瘤微环境中的交感轴突。因此，我假设PD环境 通过调节交感神经的活性和神经来产生变化的黑色素瘤反应 在肿瘤微环境中。为了调查这一点，我首先是表征黑色素瘤进展及其 WT和LRRK2-G2019S-KNOCK（GSKI）小鼠中的神经微环境。数据显示了程度和 在GSKI小鼠中，黑色素瘤生长的模式显着改变，免疫标记的肿瘤显示出改变 神经，巨噬细胞浸润和血管生成的模式。这些和其他数据将用于 确定测试LRRK2-G2019S介导的黑色素瘤生长改变的条件和时机 位于局部交感神经活动的下游，并确定是否可以逆转阳性结果 LRRK2激酶活性的抑制作用，该活性与G2019S突变显着升高。研究 肿瘤微环境中交感神经活动和神经支配的下游影响将产生 对连接PD和黑色素瘤的神经机制的更深入了解。