Vishal Chandra, OUHSC
Localized delivery of SHetA2 for prevention of endometrial carcinogenesis (Funded 2021 - 2024)
ABSTRACT
Amongst all the gynecological malignancies, endometrial cancer (EC) is only cancer, which has increasing rate of incidence from last decade. The increasing incidence of EC is mainly ascribable to a parallel increase in the incidence of obesity. Although, endometrial cancer is associated with a fairly good prognosis in comparison to other cancers, surgery remains the cornerstone of management. However, surgery is not a good option for obesity and obesity-related co-morbid conditions, and women of childbearing age, which prevents individual’s candidacy for surgical operation. Therefore, prevention strategies are needed to reduce costs and distress due to current treatment options in patients and their families. Reversion of EC precursor lesions such as atypical endometrial hyperplasia (AEH/EH) to normal endometrium is a rational approach to prevent EC development and reduce endometrial cancer mortality and morbidity. SHetA2, a novel, nontoxic, small molecule, is acting through Grp75 and causes cyclinD1 degradation, leading to G1-cell-cycle arrest and induces apoptosis in only cancer cells including EC. However, the potential efficacy of SHetA2 is limited by its low oral-bioavailability due to poor aqueous solubility. Vaginal suppository system has been shown to achieve predicted local therapeutic effective drug concentrations at the cervix for potential treatment of cervical dysplasia. Further, levonorgestrel-releasing-intrauterine system was found to be more effective than oral-progesterone for AEH treatment, demonstrating the utility of this delivery system in patients with endometrial pathology. Therefore, we hypothesize that an intrauterine-polymer rod drug-delivery system will be better option for delivering SHetA2 to overcome its limited oral-bioavailability and release a local dose sufficient to treat and prevent AEH progression. We postulate that SHetA2 will repress EC by 1) degrading cyclinD1, thereby inhibiting cell-cycle progression and 2) interrupting Grp75-mediated estrogen-receptor migration to mitochondria and thus, restarting the suppressed apoptotic activity of precancer and cancer cells. In this research proposal, we aim to develop an intrauterine-drug-eluting polymer system to deliver SHetA2 at sustained doses for long-term to the endometrium and evaluate the biological activity and safety of SHetA2 in our lab generated estrogen-mediated AEH rat model. Overall, this project is designed to understand the efficacy of SHetA2 when deliver locally at the site of disease to prevent and treat AEH, thereby preventing the development of EC
Nesreen Alsbou, University of Central Oklahoma
Microbubbles-associated traumatic brain injury detection using portable and low-cost microwave imaging system (Funded 2021 - 2024)
ABSTRACT
The goal of this research is to use a portable and low-cost microwave imaging system to detect and prevent neural tissue damage, specifically neuroinflammation caused by microbubble-associated cavitation damage, during traumatic brain injuries (TBI). The research will focus on the detection and identifying of the microbubbles and collapsing those microbubbles immediately after TBI using in vitro and in vivo blast tube test models. The proposed project stems from our developed microwave detection system to successfully detect microbubbles after sudden agitation, which was possible from an OKINBRE mini grant. Microbubbles measured in microns can form in the cerebral spinal fluid inside the skull during traumatic brain injuries (TBI). The “formation and dramatic collapse” of these microbubbles, a process is known as cavitation, could be responsible for neural tissue damage. Many mathematical models reported that when a frontal blast wave encounters the head during TBI, a shock wave is transmitted through the skull, cerebrospinal fluid (CSF), and tissue, causing negative pressure at the contrecoup that resulted in neuroinflammation caused by cavitation damage. However, there is no in vitro and in vivo experimental evidence that confirms the microbubble creation and collapsing. This study will first conduct shock tube experiments to determine whether microwave can detect cranial cavitation from realistic IED non-impact blast loading using an ellipsoid filled with degassed water to simulate tissue. Shock tube tests will be conducted on two mice head/brain invitro models. First model simulates the tissue as a fluid and second model simulates the tissue as a viscoelastic material surrounded by a layer of water simulating the CSF. The presence or absence of cavitation via high-speed video will be verified with microwave intensity data. Second, the study will conduct shock tube experiments on mice to detect the neuroinflammation induced by cavitation damage using our microwave and nuclear imaging systems. The animals’ neuroinflammation subjected to blast after 24 hours will be compared to validate the efficacy of our microwave detection system for TBI injury. We will conduct blood plasma and histopathology to determine whether there is any correlation between biomarkers and microwave detection intensity.
Tomoharu Kanie, OUHSC
Characterization of the ciliary vesicle in cilium biogenesis (Funded 2021 - 2024)
ABSTRACT
The primary cilium is a sensory organelle that extends from the cell surface and functions as a signaling hub for numerous extracellular signals, including the Hedgehog signaling pathway. Defects in the primary cilium causes a variety of disorders collectively termed ciliopathies. These disorders range from developmental defects to obesity and retinal degeneration. Understanding the physiological roles of the primary cilium and the mechanisms underlying ciliopathies requires the identification and characterization of the genes required for formation and the function of the primary cilium. Yet, the drivers of ciliary biogenesis and function remain largely uncharacterized. To fill this gap, studies in my laboratory will focus on elucidating the molecular mechanisms involved in the formation of the primary cilium. The earliest known step of the cilium biogenesis is recruitment of the small vesicle, so called ciliary vesicle, to the mother centriole. The ciliary vesicle was first described in 1962, yet protein and lipid constituents of the vesicle, the mechanism of its biogenesis and its trafficking are largely unknown. In this proposal, I will seek to answer these unsolved biological questions. Specifically, in Aim1 I will purify the ciliary vesicle by three independent but complementary approaches: i) Subcellular fractionation ii) Immuno-capture of the vesicle, and iii) Isolation of centrosomes that possess ciliary vesicles by detergent-free purification. In Aim2, I will identify regulators of ciliary vesicle trafficking using the publicly available CRISPR screen data for cilium function. Using bioinformatics approaches, I have narrowed down a set of 29 proteins as potential regulators for ciliary vesicle trafficking. We will test if these proteins localize to membrane compartments involved in vesicle trafficking and if they are required for ciliary vesicle recruitment and subsequent cilium biogenesis. When completed, this study will identify new components of the mysterious vesicle and regulators of its trafficking, and will expand our understanding of the molecular mechanisms of cilium biogenesis.
Cammi Valdez, NSU
Investigating diabetic retinopathy: New tool and mouse model development (Funded 2021 - 2024)
ABSTRACT
The prevalence of diabetes continues to rise in the U.S. with more than 34 million cases and an additional 88 million patients with prediabetes (CDC 2020). Diabetic retinopathy (DR) is a common microvascular complication of diabetes that leads to vision loss and blindness in >10% of patients (CDC 2020). Thus, a better understanding of the underlying mechanisms that drive DR development are needed to seek alternative treatment options. The tight regulation of the cells associated with capillaries, endothelial cells and pericytes, is necessary for microvascular integrity and function in the retina. Previous work by the applicant has shown that disruption of the capillary cellular ratio via direct pericyte loss leads to the microangiopathies associated with DR (Valdez 2014). Established in the 1961 by Cogan and Kuwabara, the trypsin digest (now elastase digest) is the gold standard in the field of DR for assessing post-mortem vascular microangiopathies. The quantification of endothelial cells and pericytes is determined by cell morphology, however the distinction between these two cell types is more challenging in the smaller vasculature of the mice (Cuthbertson 1986). To eliminate human error or bias, this proposal aims to develop an open-source automated image analysis program for the detection and quantification of endothelial cells and pericytes in the retinal microvasculature that is adaptable to various microscopes and species. The mechanism by which DR develops is still not fully understood. It is generally accepted in the DR field that hyperglycemia, as well as length of diabetes, leads to the progression of DR. Beyond this, there are many reports pointing to a specific role for fructose as the stimulant of the signaling cascade that leads to the microvascular damage found in DR (Cohen 1972; Solomon 1979; Kearney 2014; Fenwick 2018). However, the direct role of fructose in the development of DR has not been experimentally pursued in animal models. Therefore, we will develop and characterize a high fructose diet mouse model, fructosemia, to determine the involvement of fructose in the progression of DR. Taken together, these aims will allow us to develop two new tools to elucidate the mechanisms driving the development of DR.
Mohammad Hossan, UCO
Flow analysis of a bioresorbably pipeline embolization device for treatment of aneurysms (Funded 2020 - 2024)
ABSTRACT
Cerebral aneurysm with poorly understood hemodynamic pathology is one of the deadly vascular diseases with a higher mortality and morbidity rate upon rupture. Recently, finely braided flow diverters (FDs) have become popular as effective endovascular devices for the treatment of aneurysms with better clinical outcomes. FD regulates blood flow to induce biological responses and serves as a scaffold for vascular remodeling. However, post-treatment challenges such as late thrombosis, rupture, intra-cerebral hemorrhages (ICH), incomplete occlusion, and higher mortality rates are still unresolved. The permanent placement of non-degradable FDs is considered to be one of the sources for many of these complications. In addition, the correlations among FD designs, FD regulated hemodynamics, and their biological responses for intra-aneurysmal thrombus formation and healing processes are still unknown and underexplored. Hence, the specific aim 1 of this proposed research is to Investigate mechanobiological characteristics of flow diverter-induced intra-aneurysmal thrombus using a silicon aneurysm model. Rheological and biological characterization of FD induced intra-aneurysmal thrombus and its formation mechanism will be studied. The specific aim-2 is to Analyze the in-vivo performance of bioresorbable poly(ε-caprolactone) (PCL) flow diverters in a Rabbit saccular aneurysm model. An aneurysm will be created in the right carotid artery of the rabbit to analyze the efficacies of the non-braided PCL flow diverter. This project will provide fundamental insight in understanding FD regulated biological responses and their optimization through FD designs. The success of bioresorbable FDs will have a paradigm shift in endovascular treatments of CAs. The novelty of the proposal is a) development of bioresorbable non-braided FDs and b) critical understanding of FD engineered intra-aneurysmal thrombi. As an immediate translational application, the developed FDs can be used as coronary stents to support stenosed/thrombosed blood vessels.
Maria Ruiz Echevarria, OUHSC
RNA interference (RNAi) of global androgen signaling targeting prostate cancer (Funded 2020 - 2024)
ABSTRACT
In this proposal, building on the concept that small regulatory RNAs (miRNAs, siRNAs, endogenous shRNAs) collectively inhibit numerous targets within functional gene networks to exert biological effects, we have developed a screening platform to find shRNAs that target groups of AR-coregulators critical for prostate cancer survival/progression. The experiments proposed here will allow us to link specific shRNAs to the AR-signaling pathway, and to uncover relevant groups of AR-coregulators by empirical determination of the direct shRNA targets and their effect on AR-signaling. Implementation of our shRNA-based screen in several prostate cancer cell lines has led to the identification of strong candidate shRNAs, that when expressed individually, inhibit prostate cancer cell viability/growth (toxic). Since AR-signaling is essential for prostate cancer cell viability, we hypothesize that toxic shRNAs directly target groups of AR-coregulators, inhibiting global AR-signaling and leading to loss in cell viability. Computational analysis confirmed that the toxic shRNAs target multiple known AR-coregulatory genes. Guided by this preliminary data, we will rigorously determine the ability of the toxic shRNAs to inhibit global AR-signaling and whether this is linked to their effect on prostate cancer cell viability (Aim 1). AGO-CLIP analysis combined with gene expression and computational analysis, will define the direct targets of the toxic shRNAs. Analysis of clinical data will guide the identification and selection of the most relevant coregulators that will be validated by their ability to modulate AR-signaling. (Aim 2). In the long term, we expect this research to provide more effective therapeutic strategies for prostate cancer.
Horrick Sharma, SWOSU
Development of small molecules targeting cancer metabolism (Funded 2019 - 2024)
ABSTRACT
Pancreatic cancer will become the second-leading cause of cancer-related deaths in the U.S by this decade. Metabolic reprogramming and metabolic plasticity are emerging as major determinants of pancreatic cancer's growth and metastasis. Recent efforts have led to discovering compounds that inhibit lactate dehydrogenase-A, LDHA, a key glycolytic enzyme that mediates the Warburg effect in cancer cells. However, none of these inhibitors has advanced to clinical trials. New studies show that inhibition of both isoforms of lactate dehydrogenases, LDHA and LDHB, may be needed for effective inhibition of tumorigenesis. So far, only two potent and specific dual inhibitors are known in the literature. This proposal aims to improve the potency of existing lead LDHA/LDHB inhibitors to-submicromolar/nanomolar concentrations, evaluate metabolic stability and toxicity, and in vivo efficacy in animal cancer models. The following are the specific aims of this proposal: Aim 1 will employ molecular modeling and iterative medicinal chemistry to design and synthesize compounds with improved potency. Aim 2 will characterize and validate the LDH inhibitory and anticancer activity of compounds synthesized in aim1. Further, to incorporate drug-like features, solubility, chemical and enzymatic stability, and metabolic properties will be determined to prioritize molecules for in vivo studies. Aim 3 will determine in vivo efficacy and toxicity of potential lead compounds. Further, the synergistic effect of lead LDH inhibitor with OXPHOS inhibitor metformin and with gemcitabine, one of the first-line drugs for the treatment of advanced pancreatic cancer, will be studied in vitro and in vivo. This proposal, if successful, will lead to the development of a first-inclass LDH inhibitor for a more comprehensive preclinical study to advance new therapeutic options, combining novel drug targets for pancreatic cancer.
PAST OK-INBRE RESEARCH PROJECT INVESTIGATORS
Naushad Ali, OUHSC
Tasquinimod and Nivolumab Combined Immunotherapy for Liver Cancer (Funded 2019 - 2021
Shaoning Jiang, OUHSC
Developmental programming of mitochondrial biogenesis in maternal diabetes: Role of AMPK (Funded 2019 - 2021)
Scott Mattison, UCO
Optical coherence vibrometry guided design of computational cochlear mechanics models (Funded 2019 - 2021
Sapna Das-Bradoo, NSU
Role of Mcm10 in the maintenance of genome stability (Funded 2016 - 2021)
Lauren Zenewicz, OUHSC
Regulation of C. difficile infection by the cytokine interleukin-22 (IL-22) (Funded 2016 - 2020)
Lilian Chooback, UCO
Development of new antibiotics: Inhibiting Escherichia coli dihydrodipicolinate S (Funded 2016 - 2019)
Zachary Dalebroux, OUHSC
Salmonella cardiolipins for resistance and evasion of innate immunity (Funded 2016 - 2019)
Kyeorda Kemp, NSU
Elucidating the mechanism of how 4µ8c effects type 2 cytokines (Funded 2016 - 2018)
Mohiuddin Ahmad, OUHSC
Septo-hippocampal circuitry in mouse models of neurodevelopmental disorders (Funded 2015 - 2019)
J. Kimble Frazer, OUHSC
Molecular mechanisms of oncogenesis and treatment resistance in Burkitt Lymphoma (Funded 2014 - 2019)
Morshed Khandaker, UCO
Effect of nanoscale surface treatments on the biomechanical performances of titanium implant (Funded 2014 - 2019)
Joseph Ahlander, NSU
Ard1 control of cell survival and cancer progression in drosophila (Funded 2014 - 2016)
Noah Butler, OUHSC
Memory T cell-mediated protection against malaria (Funded 2014 - 2016)
Susana Chavez-Bueno, OUHSC
Identification of virulence factors in E coli strains causing neonatal sepsis (Funded 2014 - 2016)
Anna Csiszar, OUHSC
IGF-1, NDA repair and neoplasia (Funded 2014 - 2015)
Jicheng Fu, UCO
Personalized pressure ulcer prevention for spinal cord-injured wheelchair users (Funded 2011 - 2016)
Kevin Wang, NSU
Low cost clot-dissolving protein from transgenic plants for stroke treatment (Funded 2011 - 2016)
M. Omar Faruk Khan, SWOSU
Cyclen based novel antimalarial agents (Funded 2011 - 2014)
Jennifer Peck, OUHSC
Arsenic exposure and gestational diabetes (Funded 2011 - 2014)
Christopher Sansam, OMRF
TopBP1 complexes in DNA replication and the chemotherapy response (Funded 2011 - 2013)
Yih-Kuen Jan, OUHSC
Autonomic and microvascular functions and pressure ulcers in spinal cord injury (Funded 2011 - 2012)
Wei-Qun Ding, OUHSC
The Role of SOD-1 in Docosahexaenoic Acid-Induced Cytotoxicity in Cancer Cells (Funded 2009 - 2014)
Cindy Cisar, NSU
Antibiotic Resistance in Coliforms (Funded 2009 - 2011)
Igor Dozmorov, OMRF
Functional Signature of Multidrug Resistance of Bladder Tumor Cells (Funded 2009 - 2011)
Jaehoon Seong, UCO
MRI Flow Study in the Silicone Replicas of Human Carotid Bifurcation with Age (Funded 2009 - 2011)
John West, OUHSC
Vaccine-Targeted Identification of Fitness Determinants in the HIV-1 Envelope (Funded 2009 - 2011)
Jessica Martin, NSU
Isolation and Structural Characterization of Marine Fungal Siderophores (Funded 2007 - 2014)
Tim Hubin, SWOSU
Development and Screening of Transition Metal Complexes as CXCR4 Antagonists (Funded 2006 - 2011)
Susannah Rankin, OMRF
Sister Chromatid Cohesion and the Origin of Tetraploidy (Funded 2006 - 2011)
Dennis Frisby, CU
Regulation of Chlinergic Function in Caenorhabditis elegans (Funded 2006 - 2009)
Christopher Pritchett, NSU
Identification of Mycobacterium Marinum Virulence Genes Using a Modified STM Protocol (Funded 2006 - 2007)
Deborah Stearns-Kurosawa, OMRF
In Vivo Localization of Anthrax Toxins by Magnetic Resonance Imaging (Funded 2006 - 2007)
Wei Chen, UCO
Mechanistic study on synergistic photo-immunological effects of laser immunotherapy for metastatic cancers (Funded 2004 - 2009)
Carla Guthridge, CU
Characterization of NAG Expression and Functions (Funded 2004 - 2009)
Jason Johnson, SWOSU
Mechanisms of Synchronization: Vestigial Paths to Urea Cycle Deficiences? (Funded 2004 - 2009)
William McShan, OUHSC
Regulation of Mismatch Repair in Streptococus Pyogenes (Funded 2004 - 2009)|
Lurdes Queimado, OUHSC
The Role of MMS19 in DNA Repair and Trnascription (Funded 2004 - 2009)
Arden Aspedon, SWOSU
Identification and characterization of molecular genetic determinants mediating osmoadaption in pseudomonas aeruginosa (Funded 2004 - 2006)
Nancy Paiva, SE
Study of the biosynthesis of medicinal and nutritional plant metabolites using functional genomics and bioinformatics (Funded 2004 - 2006)
Rheal Towner, OMRF
Can antioxidants prevent brain tumor development?: In vivo magnetic resonance (MRI/MRS) evaluation (Funded 2004 - 2006)
Karen Wendel, OUHSC
Differences in vaginal microbial ecology in women with and without bacterial vaginosis (Funded 2004 - 2006)
Sonya Williams, LU
Characterization of microglial expression of cytokines as a result of age related loss of E2 (Funded 2004 - 2006)