The Psychoneuroimmunological Consequences of Cancer and Cancer Survivorship

DESCRIPTION（由申请人提供）：对于以前的癌症经历对大脑和行为的持久和普遍后果的持续时间，原因或机制知之甚少。这项工作的长期目标是确定中枢神经系统外的癌症在癌症期间和成功治疗后如何影响大脑生理，从而影响大脑功能。作为我们追求长期目标的第一步，R03项目的总体目标是为后续的NCI R01应用收集初步数据，并通过创建肿瘤切除的“存活”小鼠模型，开发已建立的肿瘤模型方法的创新扩展。该项目的中心假设是，小鼠乳腺肿瘤诱导小胶质细胞介导的神经炎症，损害学习和记忆，这两种情况都可以通过肿瘤切除得到改善。我们提出了两个特定的目的来验证中心假设，即使用非转移性乳腺癌小鼠模型和乳腺癌“生存”（即完全切除肿瘤）。目的1是确定肿瘤发展和肿瘤切除后认知行为的改变。根据我们的初步数据，工作假设是外周肿瘤诱导特定的学习和记忆障碍，通过标准化的啮齿动物行为测试来测量，而肿瘤切除会减弱这些障碍。目的2将确定与认知相关的神经改变，并与肿瘤生长或肿瘤切除一致。这一目标的工作假设是，周围肿瘤触发小胶质细胞介导的神经炎症（例如，促炎细胞因子、NF-κ b、吲哚胺-2,3脱氧酶mRNA和蛋白表达升高以及激活的小胶质细胞形态），同时伴有学习和记忆障碍。Aim 1的预期结果是识别认知行为的特定类型或组成部分，这些类型或组成部分仅受cns外肿瘤的存在的影响，或者在使用新的肿瘤模型切除肿瘤后仍然存在。目的2将为这些行为变化背后的机制神经通路提供基础。这一贡献将是重要的，因为它将为癌症和幸存者相关认知问题的干预提供神经炎症特异性目标的见解，这在人类研究中是不可能的。在我们看来，拟议的研究是创新的，因为它建立了一个乳腺癌幸存者的模型，通过这个模型来调查与迅速扩大的癌症幸存者人口相关的问题。这项提议的研究还具有创新性，因为它将开始描述癌症、癌症治疗和癌症相关压力在癌症相关认知变化中的作用。

DESCRIPTION (provided by applicant): Little is known about the duration, causes, or mechanisms underlying the enduring and prevalent consequences of a previous cancer experience on the brain and behavior. The long-term goal for this work is to determine how cancer outside of the CNS affects brain physiology and, therefore, brain function, both during cancer and after successful cancer resolution. The overall objective of this R03 project, as the first step in pursuit of our long-term goal, is to harvest preliminary data for the succeeding NCI R01 application and to develop an innovative extension of established tumor model methodology by creating a tumor resected "survivor" mouse mod- el. The central hypothesis for this project is that mouse mammary tumors induce microglial-mediated neuroinflammation and impair learning and memory, both of which are ameliorated by tumor resection. Two specific aims are proposed to test the central hypothesis using a non-metastatic mouse model of breast cancer and breast cancer "survival" (i.e., complete tumor resection). Aim 1 is to identify alterations in cognitive behavior during tumor development and post-tumor resection. Based on our preliminary data, the working hypothesis is that peripheral tumors induce specific learning and memory impairments as measured by standardized rodent behavioral tests, whereas tumor resection attenuates these impairments. Aim 2 will determine neural alterations relevant to cognition and coincident with tumor growth or following tumor resection. The working hypothesis for this aim is that peripheral tumors trigger microglial-mediated neuroinflammation (e.g., elevations in pro- inflammatory cytokines, NF-κB, indolamine-2,3-deoxygenase mRNA and protein expression and activated microglial morphology) coincident with learning and memory impairments. The expected outcome for Aim 1 is the identification of specific types or components of cognitive behavior that are influenced solely by the presence of an extra-CNS tumor or which remain after tumor resection using a new tumor model. Aim 2 will provide the foundation for the mechanistic neural pathways underlying these behavioral changes. This contribution will be significant because it will provide insight into neuroinflammation-specific targets of intervention for cancer- and survivor-associated cognitive problems, which is not possible with human research. The proposed research is innovative, in our opinion, because it establishes a model of mammary cancer survivorship by which to investigate questions relevant to the rapidly expanding population of cancer survivors. The proposed research is also innovative because it will begin to delineate the roles of cancer, cancer treatment, and cancer-associated stress in cognitive changes related to cancer.