This application is focused on the study of the mechanisms by which chemotherapeutic drugs impact the cognitive function of cancer patients. Millions of people are diagnosed with cancer every year, and more than 60% of these now survive for 20 years, with severely diminished quality of life due to treatment-induced cognitive impairments. I am a fully trained neuro-oncologist, with a solid background in the lab, where I studied both mitochondrial and brain tumor biology. Over the past years, I recognized the importance of chemotherapy- induced cognitive defects and became passionate about finding the biological explanations for this major pathology. A.
The specific aims of this proposal will focus on two DNA-targeting compounds that are widely used in oncology - cisplatin and temozolomide;
we aim to explore the mechanisms by which these drugs provoke learning and memory defects. The ultimate goal of these studies would be to prevent or counteract these adverse effects.
Aim 1) To determine the relative vulnerability of neural progenitor cells and mature neurons to clinically-relevant doses of cisplatin and temozolomide, using in vitro systems.
Aim 2) To determine the mechanism by which cisplatin and temozolomide injure neuronal cell populations, testing if these mechanisms involve mitochondrial dysfunction.
Aim 3) To examine the effects of acute and chronic graded cisplatin and temozolomide doses on vulnerable neuronal populations in vivo, and to study the role of this cellular injury in learning and memory defects.
Aim 4) To examine if chemotherapy-induced cognitive deficits can be ameliorated by an intervention that augments neurogenesis and dendritic spine growth / stability, i.e., BDNF enhancement using ampakines. B. My career plan is to conduct the research proposed in the nurturing environment offered by the University of California, Irvine. This includes my mentor, an internationally known neuroscientist/clinician (Prof. Tallie Z. Baram), my co-mentor, an international leader in oncology (Prof. Frank Meyskens), my supportive chair and dean, protected research time, and excellent collaboration from my clinical colleagues. My immediate career goal is to immerse myself in cutting-edge neuroscience that will facilitate my understanding of the mechanisms by which cancer treatments impact the brain. This will be accomplished via basic neuroscience courses, hands-on methods, lab meetings, national meetings and intensive self-study. My long-term goals are to assume a senior role in my lab, acquire the skills necessary for productive publications, enlarge my research group, apply successfully for R01 funding and receive tenure. Finally, I want to enhance my involvement in the neuroscience community and to generate an independent, creative, translational research program. In summary, my goal is to develop cutting-edge bench-to bedside research focused on the biological mechanisms underlying the prominent cognitive deficits caused by chemotherapy, and to reverse this process. This grant will provide me with the necessary funding and mentorship to become a successful, independent researcher.
Learning and memory defects induced by chemotherapeutic drugs are rapidly emerging as major clinical problem, as one and a half million people are diagnosed with cancer every year in the US, and more than 60% of these now survive for 20 years or more. Chemotherapeutic drugs may affect cognitive function via several potential mechanisms, such as killing sensitive neural progenitor cells (stem cells) or injuring existing neurons, especially the vulnerable parts of brain cells that are involved in learning and memory formation (dendrites and dendritic spines). The specific aims of this proposal focus on two medications used widely in cancer care and explore the potential mechanisms by which they provoke learning and memory defects, with the ultimate goal to prevent or counteract these adverse effects of cancer therapy with interventions that can be used in the clinic.
|Lomeli, Naomi; Di, Kaijun; Czerniawski, Jennifer et al. (2017) Cisplatin-induced mitochondrial dysfunction is associated with impaired cognitive function in rats. Free Radic Biol Med 102:274-286|
|John, Tami; Lomeli, Naomi; Bota, Daniela A (2017) Systemic cisplatin exposure during infancy and adolescence causes impaired cognitive function in adulthood. Behav Brain Res 319:200-206|
|Yan, Huaming; Romero-López, Mónica; Benitez, Lesly I et al. (2017) 3D Mathematical Modeling of Glioblastoma Suggests That Transdifferentiated Vascular Endothelial Cells Mediate Resistance to Current Standard-of-Care Therapy. Cancer Res 77:4171-4184|
|Nolen, Shantell C; Evans, Marcella A; Fischer, Avital et al. (2017) Cancer-Incidence, prevalence and mortality in the oldest-old. A comprehensive review. Mech Ageing Dev 164:113-126|
|Di, Kaijun; Lomeli, Naomi; Wood, Spencer D et al. (2016) Mitochondrial Lon is over-expressed in high-grade gliomas, and mediates hypoxic adaptation: potential role of Lon as a therapeutic target in glioma. Oncotarget 7:77457-77467|
|Nolen, Shantell C; Lee, Brian; Shantharam, Shruti et al. (2016) The effects of sequential treatments on hippocampal volumes in malignant glioma patients. J Neurooncol 129:433-441|
|Andres, Adrienne L; Gong, Xing; Di, Kaijun et al. (2014) Low-doses of cisplatin injure hippocampal synapses: a mechanism for 'chemo' brain? Exp Neurol 255:137-44|
|Di, K; Linskey, M E; Bota, D A (2013) TRIM11 is overexpressed in high-grade gliomas and promotes proliferation, invasion, migration and glial tumor growth. Oncogene 32:5038-47|