With earlier-stage cancer diagnosis and improved efficacy of chemotherapy, doxorubicin-induced cardiotoxicity has increasingly become a significa nt cause of morbidity and mortality among cancer survivors. For example, the cardiac mortality of long-term pediatric cancer survivors is estimated to be more than eight times higher than expected. A major challenge in reducing therapy-associated cardiotoxicity is the paucity of knowledge about the molecular players and pathways that can mitigate the undesired effects of doxorubicin on myocardium.

Approximately, 15-20% of all breast cancers account for triple negative breast cancers (TNBCs) that exhibit aggressive, distinct metastatic pattern and poor prognosis resulting in disproportionate number of breast cancer deaths. Despite, a better chemotherapy response rate in early-stages, >60% of patients with TNBCs develop chemoresistance leading to early relapse and shorter survival. Understanding the mechanisms underlying such resistance is therefore crucial for the development of new, efficacious cancer drugs.

The goal of this pilot grant is to graft dopaminergic neurons into marmosets and develop MRI and PET imaging techniques to visualize the grafts and dopaminergic innervation.

The goal of this pilot grant is to derive iPSCs from marmosets using the retrovirus and episomal reprogramming techniques, differentiate them into neurons and develop transplantation strategy in marmoset model of Parkinson’s disease.

Basic Research

Instruction

This application is in response to RFA-AT-14-003, 'Clinical trials and interventional studies of non- pharmacological approaches to managing pain and co-morbid conditions in U.S. Military personnel, Veterans, and their families.' Rates of chronic pain have steadily increased among service members deployed for Operations Enduring Freedom (OEF), Iraqi Freedom (OIF), and New Dawn (OND).

DNA hypermethylation of promoter CpG islands is known to be associated with transcriptional silencing in endometrial cancer. We recently identified a unique set of CpG island loci that are hypermethylated in non- recurrent tumors but coordinately hypomethylated (or less methylated) in primary tumors that subsequently recurred. The loci can be highly susceptible to de novo DNA methylation (i.e., a default state) partly attributed to the high expression of DNA methyltransferase 1 (DNMT1) and Polycomb Repressor Complex 2 (PRC2).

The overall goal of the proposed training program is to train physician scientists for careers in translational biomedical imaging research. This goal will be met through a unique 6-year, residency/PhD training program, which combines a radiology residency with a doctoral degree in imaging science (Rahal et al., 2007). This training program is hosted by the University of Texas Health Science Center at San Antonio (UTHSCSA), a large, research-oriented institution with outstanding imaging-research resources and a long history of federally funded, imaging research.

Exposure to gadolinium-based magnetic resonance imaging (MRI) contrast is a major risk factor in the acquisition of nephrogenic systemic fibrosis (NSF), a severely debilitating disease first recognized in patients with acute or chronic renal impairment. MRI contrast agents heretofore were considered safe in these patients and thus indiscriminately used. Gadolinium-based contrast agents remain a mainstay for MR imaging and alternatives are still lacking.