Deciphering the Transcriptomic Basis of Chemo Fog

Beth Israel Deaconess Medical Center, Boston MA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT CANDIDATE: My long-term career objective is to lead an independent research program dedicated to improving the efficacy of cancer treatments and the post-treatment experiences of cancer survivors. This proposed research represents a convergence of my research experiences: to elucidate the transcriptional mechanisms underpinning cognitive impairment induced by cancer therapies, a critical issue affecting cancer survivors. In preparation for this transition to independence, I have curated a training plan encompassing four key objectives: (1) acquiring essential skills, (2) forging strategic scientific collaborations, (3) honing professional development, and (4) ensuring a seamless transition to independence. This proposal serves as a blueprint for my future research career in the field of cancer biology. RESEARCH: Chemotherapy, despite its life-saving potential, often leads to debilitating side effects such as cognitive impairment, significantly diminishing the quality of life for cancer survivors. Multiple studies have identified disturbances in brain cell homeostasis upon chemotherapy treatment, including neuronal death, disrupted myelination, and activated microglia. However, the transcriptional regulation governing these changes remains largely unclear. My early postdoctoral research revealed substantial transcriptional overlaps shared among various forms of cognitive impairment, including aging, Alzheimer's disease, and severe COVID-19. Yet, whether this transcriptional overlap, and more crucially, its regulatory mechanisms, extend to chemotherapy-induced cognitive impairment (CICI) remains unknown. Through comparative analysis of brain transcriptomic profiles of mice upon systemic chemotherapy treatment and other forms of cognitive impairment, I have identified candidate transcription factor drivers of CICI. This proposal will test the hypothesis that transcriptomic states (Aim 1) and key underlying transcription factor regulators (Aim 2) can be manipulated to modify CICI behaviors in mice (Aim 3). These investigations will illuminate the transcriptional underpinnings of cognitive impairment induced by chemotherapy, offering new insights into potential therapeutic strategies to ameliorate or reverse this debilitating side effect. ENVIRONMENT: The Harvard Medical School community provides an optimal setting for me to achieve my training and research objectives while successfully transitioning to an independent faculty position. My mentors, Dr. Frank Slack and Dr. Clifford Woolf, are global leaders in RNA biology and neuroscience, respectively. Additionally, I have assembled an advisory committee comprising three established scientists—Drs. Rosalind Segal, Winston Hide, and Marcia Haigis—with pertinent expertise and strong commitment to mentorship. Their support will be invaluable in guiding my research endeavors and facilitating my path toward independence. Combined with the intellectually rich and resource-abundant communities of BIDMC and BCH, this mentorship team will foster an ideal environment, enabling me to effectively execute the proposed research and transition to independence.