The University of Texas Health Science Center at San Antonio (UT Health San Antonio) recently received $1.5 million from the William and Ella Owens Medical Research Foundation to fund eight faculty members and their projects to advance research into pediatric and pancreatic cancers and Alzheimer’s disease.
“Since its founding in 1998, the William and Ella Owens Medical Research Foundation has generously supported research efforts at UT Health San Antonio. These grants are solely focused on original research efforts towards the causes close to the Foundation’s heart – towards cures, treatments or prevention of human disease and disorders with a special emphasis on specific cancers as well as Alzheimer’s disease,” said Lindsay Helsel, director of corporate and foundation relations in the university’s Office of Institutional Advancement. “Through their significant investments in novel research, our faculty are committed to making lives better and making a difference in understanding with the potential to translate their research findings into future treatments and therapeutics for these complex conditions.”
This year’s recipients of the awards with their project titles and synopses include:
Manzoor Bhat, PhD, professor and vice dean for research in the Department of Cellular and Integrative Physiology.
Project: Investigate the role of microglial Ms4a6c in β-amyloid-associated Alzheimer’s disease
Synopsis: This study is about Alzheimer’s disease (AD), a type of neurodegenerative disease that affects millions of people globally and is the leading cause of dementia in elderly. In this proposal, we will investigate the role of human MS4A6A gene which has been reported to be a risk factor for AD. Our innovative approaches combining both in-vivo mouse and in-vitro cell cultures and biochemical studies will provide valuable insights into mechanisms underlying AD pathogenesis and pave the way for designing novel AD treatments in the future.
Sandeep Burma, PhD, professor and vice chair for research in the Departments of Neurosurgery and Biochemistry and Structural Biology and the Mays Family Foundation Distinguished Chair in Oncology.
Project: Senescence escape as a driver for glioblastoma recurrence
Synopsis: Ionizing radiation (IR) remains the mainstay of therapy for glioblastoma (GBM) – lethal brain tumors for which approaches to improve the efficacy of radiotherapy are desperately needed. A mechanistic understanding of the basis of GBM recurrence after radiotherapy is essential to achieve this goal.
Our central hypothesis is that IR-induced senescent GBM cells undergo senescence-associated reprogramming (SAR) and acquire CSC properties and thereby contribute to tumor recurrence and that targeting senescent glioma cells or the pathways driving re-proliferation can help improve GBM therapy.
Yogesh Gupta, PhD, associate professor in the Department of Biochemistry and Structural Biology.
Project: Deciphering BAF assembly for pediatric cancer therapy
Synopsis: The adenosine triphosphate (ATP) dependent multi-subunit assemblies such as B allele frequency (BAF) (BRG1/BRM-associated factors) complexes utilize ATP hydrolysis energy to reorganize chromatin architecture and facilitate genomic accessibility to transcription factors.
However, in pediatric cancers, both assembly and recruitment of the BAF complexes are disrupted by mutations, deletions and overexpression of individual subunits, causing aberrant rewiring of BAF-mediated signaling. Moreover, aggressive childhood cancers often display molecular partnerships between defective BAFs and chimeric transcription factors. If successful, this proposal will inform novel approaches to abolish the tumor-promoting functions of aberrant BAFs.
Xianlin Han, PhD, professor in the Department of Medicine and Methodist Hospital Foundation Chair in Aging Studies and Research, Sam and Ann Barshop Institute for Longevity and Aging Studies.
Project: Myelin sulfatide deficiency alters galetin-3 signaling in Alzheimer’s disease
Synopsis: Alzheimer’s disease (AD) is the most common cause of dementia. There is minimal success for preventative treatment or cure for the disease, indicating that there is an urgent need to investigate other causal factors for AD development other than traditional Aβ and tau pathologies. In light of the increasing evidence emphasizing the importance of myelin abnormality in AD development, our lab has been studying the connections of sulfatide deficiency with AD development using sulfatide-deficit mouse models.
Therefore, in this application, we seek funds to generate a novel mouse line by crossing sulfatide-deleted mice with the line of galectin-3 deletion. The results acquired in the proposal will serve as the preliminary data for a follow-up NIH R01 application.
Sang Lee, PhD, professor in the Departments of Molecular Medicine and Radiation Oncology.
Project: Identification of APE2 nuclease inhibitors
Synopsis: BRCA1 and BRCA2 encode genes linked to breast, ovarian, prostate, pancreatic and certain pediatric cancers when inactivated. Cancer cells deficient in BRCA1 or BRCA2 can be targeted using poly (ADP-ribose) polymerase inhibitors (PARPi) as they are vulnerable to the agents that trigger excess damage to DNA, the genetic material in cells. Multiple clinical trials have been approved to successfully establish the use of PARPi for treatment of BRCA-deficient cancers. However, cancer cells often develop resistance to PARPi and we require additional targets for better treatment outcomes.
The goal of this application is to screen and identify small molecule inhibitors (SMIs) against APE2 nuclease activity by enzymatic assay-based high throughput screen (HTS) and analyze their effectiveness to kill BRCA deficient pancreatic cancers as mono- or combination therapy with little or no side effects using multiple cell biological, biochemical and biophysical assays. The results will lay the conceptual and technical foundations for an innovative strategy to target APE2 for anti-pancreatic cancer therapy and treating patients for better clinical outcomes.
Juan Pablo Palavicini, PhD, assistant professor and researcher in the Department of Medicine – Division of Diabetes, Sam and Ann Barshop Institute for Longevity and Aging Studies.
Project: Modeling late-onset Alzheimer’s via gene-environment interactions
Synopsis: Epidemiological evidence shows that humans with disturbed circadian rhythms, a consequence of shift work, jet lag, sleep disorders, or aging, have an increased risk of metabolic syndrome and other chronic diseases, including Alzheimer’s disease. Dysregulation of the circadian timing system in Alzheimer’s disease is best embodied by sleep issues and sundowning, a state of confusion that Alzheimer’s patients typically experience from dusk through night.
In this application we specifically propose to test the “non-feminizing” estrogen, 17‐α‐estradiol, at a dose that has been shown to extend median male mice lifespan by 20%. Supporting our rationale, promising pre-clinical evidence has reported that 17‐α‐estradiol also has multiple neuroprotective effects.
Muralidharan Sargurupremraj, PhD, assistant professor and researcher in the Department of Cell Biology, Genetics and Molecular Medicine and the Department of Neurology; Glenn Biggs Institute for Alzheimer’s and Neurogenerative Diseases.
Project: Exploring genome-wide gene-environment interactions: air pollution exposure, brain structure and Alzheimer’s disease
Synopsis: As people worldwide are living longer, the number of dementia cases is expected to increase drastically to 75 million by the year 2030. Alzheimer’s disease (AD) is the leading cause of dementia and there are currently no effective treatments for it. Several risk factors contribute to the development of AD and air pollution has been identified as one of the significant factors. Studies, such as the Framingham Heart Study (FHS), have found a link between exposure to air pollution, specifically fine particles (PM2.5) and changes in the brain that are indicative of AD.
Our study will specifically examine whether genetic ancestry influences the impact of air pollution on dementia risk, by exploring the differences between European and Mexican American populations. By studying how external factors such as air pollution interact with genetic factors, we aim to shed light on the onset and progression of AD, potentially guiding tailored interventions.
Pei Wang, PhD, associate professor in the Department of Cell Systems and Anatomy.
Project: Develop human CAR-T cells to treat pancreatic cancer
Synopsis: Pancreatic ductal adenocarcinoma (PDAC) represents one of the most formidable challenges with its notorious reputation for resistance to conventional treatments such as chemotherapy, radiation and even the most advanced immunotherapies. This particular cancer type creates a “cold” tumor microenvironment (TME) that effectively shields itself from the body’s immune responses. Chimeric Antigen Receptor T (CAR-T) cell therapies offer a revolutionary approach to cancer treatment by reprogramming the body’s own immune cells to recognize and destroy cancer cells. However, great improvements are needed for CAR-T therapies to be effective treatments against PDAC.
Our proposed integrative CAR-T (iCAR-T) therapy is tailor-made to confront the unique challenges presented by PDAC. This comprehensive and multifaceted approach represents a significant leap forward in the fight against PDAC. This project has the potential not only to transform the treatment landscape for pancreatic cancer but also to set a precedent for the application of CAR-T cell therapy in a wider range of cancers.
According to Mark Goldberg, MD, associate vice president for strategic research initiatives and professor of neurology, this is the second year that the institution has been invited to manage the selection of research awardees internally. Patrick Sung, DPhil, professor of biochemistry and structural biology, director of the Greehey Children’s Cancer Research Institute and interim executive director of UT Health San Antonio’s Mays Cancer Center and Sudha Seshadri, MD, professor of neurology and founding director of the Glenn Biggs Institute for Alzheimer’s and Neurogenerative Diseases, together with approximately 30 faculty reviewers, were instrumental in selecting projects with the highest prospects for sustained and impactful research in this highly competitive awards cycle.