Congratulations to faculty in the UF College of Pharmacy who received these recent research awards.
Dr. Charles Frazier and Co-I Dr. Jay McLaughlin are part of a six-month project with Alchem Laboratories Inc titled, “Evaluation of Novel Compounds Potentially Targeting Central Sigma Receptors Regarding Their Ability to Lower Blood Glucose in Diabetic Mice.” The primary objective of Phase 1 is to evaluate the potential therapeutic application of PRX-3140, a compound synthesized by Alchem Laboratories, in controlling blood glucose levels in diabetic patients. The compound is believed to exhibit activity at sigma 1 and/or sigma 2 receptors, with potential additional effects mediated by the activation of 5HT-4 receptors.
Dr. Steven Smith was awarded a five-year, $3.3 million NHLBI R01 continuation to the award titled “Antihypertensive Mechanisms of Minocycline in Resistant Hypertension: Role of the gut microbiota-brain-immune axis.” In this renewal application, Dr. Smith’s lab proposes to elucidate mechanisms that underlie the effects of minocycline on BP-lowering in White and African American individuals with TRH. The overarching objective is to test the hypothesis that minocycline rebalances gut dysbiosis, namely by increasing butyrate-producing functional capacity, attenuating gut-mediated inflammatory response and gut leakiness, and that these effects explain BP-lowering effects in TRH. Aim 1 will investigate the hypothesis that minocycline alters gut microbiota (primarily butyrate-producing capacity) that mediates minocycline-induced BP lowering in TRH. Aim 2 will assess the extent to which minocycline alters gut-associated inflammation and gut leakiness, and their response with BP changes after minocycline treatment. Aim 3 will evaluate the hypothesis that minocycline reduces neuroinflammation in TRH. Together, these studies will elucidate ANS-based mechanisms of hostmicrobiota interactions in TRH, evaluate potential of minocycline to reduce TRH, and serve as proof of concept for other therapeutic options that rebalance microbiota or mitigate TRH-associated inflammation, to improve BP control in patients with TRH, who remain at high risk.
Dr. Robert Huigens received a five-year $1.8 million NIGMS R35 renewal for the award titled “Indole Alkaloids and Halogenated Phenazines: Platforms for Discovery.” During this award, Dr. Huigens’ lab will advance their ring distortion platform using a panel of readily available indole alkaloids as starting points for the dramatic altering of their complex ring systems leveraging dearomative cycloadditions along with other chemoselective reactions. They will develop probes for transcript profiling experiments and/or target identification expeditions, as necessary. In addition, the lab has identified a series of halogenated phenazines (HP) that demonstrate potent antibacterial and biofilm-eradicating activities against critical Gram-positive pathogens. During this award, Dr. Huigens’ lab aims to expand the spectrum of activity for halogenated phenazine agents and eradicate Gram-negative bacterial pathogens through the development of new phenazine-forming reactions to incorporate primary amine moieties (following eNTRy rule guidelines) and develop HP-sideromycin agents to target specific Gramnegative species. New biofilm-eradicating agents can provide critical insights into the basic biology of Gramnegative biofilm cell viability and could lead to ground-breaking cures for persistent bacterial infections in the future.
Dr. Guangrong Zheng is MPI with contact MPI Dr. Weizhou Zhang (Pathology) on a five-year, $3.3 million NCI R01 award titled “Proteolysis targeting chimera against nuclear receptor NR4A1 for melanoma therapy.” The overarching goal is to identify targetable molecules/pathways that are critical for multiple cell types within Tumor microenvironments (TME). Proteolysis-targeting chimera (PROTAC) technology will be used to develop a first-of-its-kind NR4A1 degrader for melanoma therapy. Aim 1 is rational design of novel celastrol-based NR4A1-Ps by modifying celastrol and linkers; aim 2 is to determine cellular and molecular mechanisms by which NR4A1-Ps work to inhibit melanoma. Aim 3 is to explore the therapeutic potential of NR4A1Ps as a single agent or in combination. The outcome is to define the rationale for the future clinical translation of NR4A1-Ps to enhance ICI therapy responses in melanoma.
Dr. Tom Burris was awarded $323,000 for the one-year R61 phase of a 3-year, $1.2 million NINDS R61/R33 submission titled “Screening for Nuclear Receptor TLX ligands.” The Burris lab has discovered that the orphan nuclear receptor TLX can be targeted with small synthetic ligands; such compounds may have the ability to enhance adult hippocampal neurogenesis, improve cognitive function and thus offer novel therapies for treatment of dementias including Alzheimer’s disease among others. This project focuses on developing, refining and validation of TLX assays for the purposes of performing a screen for novel TLX ligands that can be used as points to initiate optimization efforts to develop TLX agonists towards potential clinical evaluation for treatment of diseases where cognitive function is impaired.
Dr. Chenglong Li is the UF principal investigator for a two-year, $69,00 sub-award to the University of Maryland to participate in the NCI R21 award titled “Dual inhibition of PARP and STAT3 as a novel therapeutic approach for triplenegative breast cancer.” Dr. Li’s lab will be involved in the overall chemistry efforts on the project, including computational chemistry and synthetic medicinal chemistry, especially providing LLL12B for in vitro, in vivo, ex vivo evaluation.
Dr. Jane Aldrich and Co-MPI Dr. Jay McLaughlin were awarded $2.7 million to continue the four-year NINDS UG3 Phase of their award titled “Cyclic Peptides to Treat Cocaine Use Disorder.” The proposed research focuses on novel, orally active peptide KOR antagonists with the goal of optimizing lead cyclic peptides to yield candidates for further development as potential treatments for CUD and stress-induced potentiation of CUD. The UH3 phase consists of expanding the exploration of the structure-activity relationships of the lead cyclic peptides to improve their pharmacokinetic properties and enhance pharmacological potency in vivo, and perform additional safety studies needed to advance the most promising compounds into development for clinical use. The goal at the end of the proposed research is to have identified at least one analog for development as a potential treatment of CUD.
Dr. Mei He received $130,000 as a collaborator with Ervian Bio LLC on a seven-month DoD Phase I STTR titled “Novel Scalable Loading of Antibiotics in Exosomes for Bacterial Wound Infection Prevention.” Dr. He’s lab will be responsible for validating scalable and highly efficient antibiotic cargo loading into EVs using patented µDES technology platform, as well as preparing and characterizing antibiotic loaded exosomes.
