Neural Mechanisms Driving Comorbid Parkinson's and Melanoma

项目总结/摘要 一系列的流行病学研究表明，帕金森病（PD）患者在发病过程中， 患黑色素瘤的风险更高，反之亦然。然而，对这种并发症的研究很少。一 可能的汇聚点在于交感神经系统（SNS）。研究表明，激活 存在于乳腺腺癌中的交感神经轴突增加癌症生长和转移。扩展这个， 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 LRRK 2-G2019 S突变是PD最常见的遗传因素， 肿瘤微环境中的交感神经轴突因此，我假设PD环境 通过调节交感神经轴突的活动和神经支配产生改变的黑素瘤反应 在肿瘤微环境中。为了研究这一点，我首先描述了黑色素瘤的进展及其 WT和LRRK 2-G2019 S-敲入（GSKI）小鼠中的神经微环境。数据显示， 在GSKI小鼠中，黑色素瘤的生长模式显著改变，免疫标记的肿瘤显示出改变， 神经支配、巨噬细胞浸润和血管生成的模式。这些数据和其他数据将用于 建立检测LRRK 2-G2019 S介导的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，并确定是否可以通过 抑制LRRK 2激酶活性，其在G2019 S突变时显著升高。研究 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一个 更全面地了解帕金森病和黑色素瘤之间的神经机制。

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.