The etiology of chemotherapy-related cognitive impairment (CRCI) is understudied despite the growing clinical awareness of its contribution to patient morbidity. Disease-modifying therapies to ameliorate CRCI are urgently needed. However, development of these therapies is limited by an incomplete understanding of the underlying mechanisms of CRCI. The long-term goal is to identify novel cellular mechanisms that contribute to CRCI. The overall objective of this application is to identify the role of cellular senescence in CRCI and define the microglial contribution to senescence after chemotherapy exposure. The central hypothesis is that cellular senescence mediates cognitive deficits in CRCI and that microglia promote chemotherapy-induced senescence in the brain. The rationale for the proposed research is based on preliminary data showing increased expression of senescence markers in various cell populations and evidence of increased neuroinflammation in the brains of human autopsy patients with history of chemotherapy compared to controls. The central hypothesis will be tested by performing two specific aims in a mouse model of CRCI that I have developed: (1) identify the contribution of senescence to CRCI and (2) determine the role of microglia in the development of chemotherapy-induced senescence in the brain. For the first aim, CRCI will induced in transgenic p16-3MR mice to determine if ablation of senescent cells rescues the cognitive phenotype of chemotherapy-treated mice. For the second aim, microglia in a CRCI mouse model will be pharmacologically depleted with PLX5622 (an inhibitor of colony-stimulating factor 1 receptor (CSF1R) that selectively targets microglia) to determine if reducing the number of microglia rescues cognition and reduces measures of senescence after chemotherapy. In both aims, senescence in multiple cell lineages of the central nervous system (CNS) will be assessed using a variety of molecular and immunofluorescent and senescence-associated beta-galactosidase staining techniques. The approach is innovative because the powerful transgenic p16-3MR mice line will be used to identify the role of senescence in CRCI and the role of microglia in mediating chemotherapy-induced senescence in CNS populations, both of which have not been assessed to date. Furthermore, the chemotherapeutic agents used in this study are highly clinically relevant to a number of malignancies. The proposed research is significant because if chemotherapy- induced senescence in the brain adversely affects cognition, then senolytic therapies may be a promising new strategy to reduce the morbidity of CRCI. Finally, data collected from this proposal will form the basis of my future K08 application and my research focus as an independent clinician scientist.
Chemotherapy-related cognitive impairment (CRCI) is observed in up to 80% of chemotherapy patients and results in significant morbidity. The proposed research will implement a number of molecular and immunofluorescent and senescence-associated beta-galactosidase staining strategies in a mouse model of CRCI to determine the contribution of cellular senescence to CRCI and the role of microglia in mediating chemotherapy-induced senescence in the brain. The proposed research is relevant to the mission of the NCI because the new, innovative approaches to understanding the pathophysiology of CRCI outlined in this proposal may identify pathways that can be pharmacologically targeted to ameliorate the burden of CRCI.
