Former COBRE research project leader Dr. Michy Kelly was awarded a grant through the National Institute on Aging (NIA) for her work on the role of cyclic nucleotide signaling in age-related decline of social memories.
The Center for Targeted Therapeutics hosted its' two day symposium highlighting the work down through COBRE. The featured guest speaker was Dr. Gary Landreth from the University of Indiana who spoke about his work with Alzheimer's. Also featured were presentatiions from faculty members updating their research findings. Graduate students and faculty shared posters highlighting their work and Kendall Murphy from Dr. Gower's lab won the poster award.
Former COBRE Project Leader Dr. Mythere Karthikeyan was awarded a grant through the National Cancer Institute for her work on inhibin fucnction in tumor angiogenesis.
The American Cancer Society awarded a research pilot grant for the SOAR (Supporting Outstanding Academic Research) to Dr. Mythere Karthikeyan and Dr. Eugenia Broude titled "Therapeutic Impact of Epicenetically Regulated GDF2/BMP9 in Ovarian Cancer." Grant reviewers hope that this grant wnill serve as the foundation for a R01 or similar competitive grant.
May 1, 2018
Formet Pilot Project PI, Dr. Rekha Patel's grant “Dysregulation of the PACT-mediated crosstalk between protein kinases PKR and PERK contributes to dystonia 16 (DYT16)”
August 1, 2017
“Targeting the p62 signalosome in leukemia” - Dr. Jing Fang’s new groundbreaking research addresses issues with patients with certain subtypes of leukemia associated with dismal outcomes due to resistance to current treatment options, particularly for those with MLL rearrangements. Chronic NF-kB activity is observed in leukemia cells, especially within the leukemia stem cell (LSC) population, and is implicated as a requirement for leukemogenesis, including the MLL-driven leukemia. Given the pleotropic function of NF-kB, targeting the leukemia-specific function of NF-kB is urgently needed. The proposed study will help identify and understand the function and mechanism of leukemia-specific p62 signaling pathways in the development of leukemia. This, in turn, will shape design novel targeted therapy that aims to suppress leukemia cells, but preserve normal cells.
July 1, 2017
Dr. Michy Kelly will work with other faculty at the USC School of Medicine to acquire Logos X-ClarityTM Tissue Clearing System and Confocal Microscopy Objective for the USC Instrumentation Resource Facility.
July 1, 2017
Dr. Rekha Patel is teaming up with other USC researchers to study chronic social stress and accelerated aging among South Carolina women. The team is comprised of faculty from Biological Sciences, Epidemiology and Biostatistics, Nursing, and the Arnold School of Public Health. Specifically, they will investigate the social, behavioral, and biological influences on aging processes.
Dr. Eugenia Broude, Target PI, received a NIH/NCI grant “CDK8/19 inhibitor for the treatment of HER2+ breast cancer.” The aims of this study will investigate whether Senexin B potentiates the effect of the trastuzumab/pertuzumab (T+P) combination, the current first line standard-of-care for HER2+ breast cancers, in vitro and in vivo, and whether Senexin B prevents the development of resistance to T+P. Dr. Broude’s research will test if cells selected for acquired T+P resistance and T+P treated tumors overexpress CDK8, as a possible patient selection criterion for the initial clinical development. We will also determine if treatment with T+P combined with Senexin B, in vitro and in vivo, decreases the phosphorylation of HER2- and CDK8-regulated transcription factors, as potential markers of treatment response. With approximately 20% of breast cancers characterized as HER2-positive, and patients with such cancers treated with HER2-targeting drugs (such as Herceptin), nearly 70% of patients with metastatic HER2-positive breast cancer do not respond to HER2-targeting therapy and almost all of the initially responsive cancers eventually become resistant. We have found that a non-toxic drug acting on proteins called CDK8/19 overcomes resistance to HER2-targeting drugs and prevents such resistance from developing. This research proposes a program of studies that will lead to combining this drug with HER2-targeting therapies in the treatment of patients with metastatic HER2-positive breast cancer.
With this award, “Brain targeted nanoparticle for Alzheimer's disease therapy,” Dr. Peisheng Xu and Dr. Michy Kelly will develop a NAC-DTDRN and characterize its BBB penetration efficiency in vitro and evaluate the anti-inflammatory and anti-oxidant effects of the NAC-DTDRN in vitro and study its pharmacokinetics in vivo. This study will test the efficiency of the NAC-DTDRN in an AD animal model and evaluate its toxicity. This research will develop a nanoparticle based brain targeted delivery system for the immunotherapy of Alzheimer’s disease by taking advantage the unique characteristics of the brain tissue.
COBRE Pilot Project PI, Dr. Pavel Ortinski, seeks to address the obstacle to developing effective drug addiction therapies – drug-induced plasticity is often restricted to discrete neuronal populations within brain reward areas. The goal of this research is to investigate mechanisms that assemble medium spiny neuron (MSN) microcircuits underlying behavioral expression of cocaine seeking and taking. We propose that release of neuroactive molecules from astrocytes, a type of non-neuronal brain cell, facilitates changes within neurons specifically associated with cocaine experience. Identification and isolation of neuronal populations that drive cocaine-directed behavior may facilitate development of targeted addiction therapeutics while expanding fundamental understanding of astrocyte-neuron interactions.
In his new research, “Functional identification of new mechanisms of neurotoxicity induced by HIV and drugs of abuse,” Dr. Michael Shtutman seeks to set a standard model approach for understanding how HIV and drugs of abuse promote neuronal damage and death, including both direct and indirect effects of HIV proteins in combinations with opiates and stimulants. Furthermore, these approaches can then be applied to a variety of systems from primary neuronal culture to animal models of HAND, to further explore novel therapeutic targets for treatment of HAND. HIV Associated Neurocognitive Disorder (HAND) is among the most common and clinically important complications of HIV infection. The project will determine new mechanisms of synergistic neurotoxicity of HIV Tat and cocaine, with the results leading to the discovery of new targets for the development of HAND therapy.
July 1, 2016
Dr. Rekha Patel is teaming up with other USC researchers to study the influence of mitochondrial ND5 sequence on average lifespan of Daphnia pulex. The team includes faculty from Biological Sciences and the Department of Pharmacology, Physiology, and Neuroscience from the USC School of Medicine.
May 15, 2016
COBRE Pilot Project PI, Dr. Claudia Grillo, received a NSF grant “Identifying a new circuit that controls feeding behavior: leptin and serotonin interactions.” Feeding is an essential activity for the maintenance of life, and its regulation is associated with multiple brain mechanisms that work together to ensure that animals eat appropriately. The complexity of these interactions has presented challenges to our efforts to fully appreciate the neural basis of food intake. However, before we can understand that complexity we must first identify the individual brain circuits that regulate food intake. The main goal of this project is therefore to use advanced genetic and anatomical approaches to identify a novel circuit that contributes to the control of feeding behavior. Identifying this circuit will ultimately allow us to determine how it works together with other feeding circuits that we already know more about to regulate a complex behavior critical for animal survival. In achieving that goal the work will not only increase our understanding of fundamental principles associated with how the brain regulates behavior, but may also lead to unexpected insights into feeding disorders and the chronic medical conditions associated with them that create considerable economic and social burdens, nationally and globally. In addition, this project includes a Summer Internship Program that will provide an integrated research experience for undergraduate students, particularly students who will be recruited from populations that are under-represented in science and medicine. These research experiences will provide such students with experiential learning opportunities that will create a foundation for future success in biomedical or basic research science.
September 1, 2015
Dr. Norma Frizzell’s grant hypothesizes that mitochondrial stress results in the accumulation of fumarate and that succination alters protein structure or function contributing to disease pathology. It identifies several succinated targets already and mechanistically addresses how succination of these leads to further reductions in mitochondrial function. The study will use a molecular strategy to distinguish the bioenergetic defect from protein succination and investigate therapeutic strategies designed to reduce fumarate and succination leading to improvements in mitochondrial function and the disease phenotype. This work will directly assess how a protein modification derived from a mitochondrial metabolite contributes to the development of neuropathology during Leigh Syndrome. By demonstrating the significance of this pathway in the progression of disease pathology, we will be able to design novel targeted therapeutic strategies for the effective treatment of mitochondrial diseases.
August 7, 2015
Dr. Petkov’s grant, “Role of TRP channels in human detrusor function and disfunction” will use multiple state-of-the-art approaches including single-cell RT-PCR, qPCR, Western blot, in situ proximity ligation assay, confocal immunohistochemical and immunocytochemical analyses of DSM whole tissue and single cells to identify the TRPM4 channel expression and localization in human DSM cells from control and OAB patients. The research will reveal unknown mechanisms of human urinary bladder function and regulation in health and disease.
August 1, 2015
The expansion of adipose tissue is associated with the development of insulin resistance and Type 2 diabetes. Given that ~26 million Americans have diabetes and an estimated 79 million have prediabetes, the role of expanding adipose tissue mass in the development of systemic metabolic dysfunction has received increased attention. However, many of the biochemical mechanisms underlying adipocyte metabolic dysfunction remain unclear.Dr. Frizzell’s research explores the early metabolic changes in the adipocyte and anticipates that these studies will lead to better targeted therapies for the early treatment of diabetes.
July 1, 2015
Dr. Xu’s award, “Nano-cocktail Overcomes Multidrug-Resistance for Ovarian Cancer Therapy” explores drug combinations for optimal cancer cell proliferation inhibitory effect and examines the dual-ligand targeting effect on the biodistribution of DTNC and investigate its pharmacokinetic properties. The study evaluates the tumor growth inhibitory effect of DTNC in both subcutaneous xenograft and orthotopic intraperitoneal tumor mouse models and examine its systemic toxicity. This research will develop a nano-cocktail for the treatment of ovarian cancer through a dual-targeting strategy to carrier a drug combination which can kill cancer stem cells and drug resistant cells as well as stop the metastasis of cancer.
Dr. Ho-Jin Koh, former pilot project PI, will determine TRB3 expression and function in response to skeletal muscle denervation and anticipates that overexpression of TRB3 in muscle will worsen muscle atrophy. The proposed research will establish the novel function of TRB3 on muscle atrophy and identify a new approach for treating muscle atrophy. In addition, the study will provide evidence to investigate the role of TRB3 in other muscle diseases related to muscle atrophy, including muscle disuse, cachexia, and sarcopenia. The loss of muscle mass (atrophy) is one of the medical consequences of many diseases, including cancer, neurodegenerative diseases and autoimmune diseases, and results in serious health problems. The exact causes of muscle atrophy are not known, and this study will investigate the role that a protein, TRB3, may play in mediating one type of muscle loss.
The Brain and Behavior Research Foundation awarded Dr. Michy Kelly’s grant “Dissecting the molecular and anatomical pathways of recent versus remote long-term memory.”
July 8, 2014
Dr. Michy Kelly’s study will determine where (VHIPP vs. dorsal HIPP) and when (adulthood vs. adolescence) PDE11A modulates social behaviors and identify how social isolation modifies PDE11A compartmentalization and, thus, impairs subsequent social behaviors. In addition, the research will define the signals that control the subcellular localization of PDE11A. Finally, the proposal seeks to better understand how compartmentalization of cyclic nucleotide signaling in the ventral hippocampal formation regulates social behaviors with the goal of identifying new therapeutic targets for social deficits