Programs

Pilot Project Program

The Center of Biomedical Research Excellence in Natural Products Neuroscience (COBRE-NPN) will fund up to five Pilot Program Projects of $50,000/year/project. The maximum duration of support will be 2 years. Applications must address one of the three areas of research (basic science, translational or entrepreneurial development) and the project scope must be within the COBRE-NPN thematic research focus area – understanding the neuropharmacologic effects of natural products.

Eligibility

Eligibility: All University of Mississippi faculty members are eligible to participate in the Pilot Project Program. Preference will be given to junior investigators who are in the early stages of their career. Those who have not yet received a major program grant (e.g. an R01) award are also encouraged to apply for the PPP. Past graduates from the COBRE-NPN program, who do not serve as mentors, may also compete for the projects but will have to present a compelling rationale to be considered for funding.

Project areas that fall within the scientific focus of the CORE-NPN include but are not limited to: 

    • Basic science research: biological evaluation of natural products as agents possessing neuropharmacologic effects.
    • Translational science research: Translating basic science discoveries from animal models to human subjects.
    • Commercialization (Entrepreneurial development): The advancement of research discoveries from the bench to the commercial sector.

Criteria

Criteria for evaluation of COBRE application:

    • Initial evaluation will be done based on the cover page and specific aims submitted by all applicants and will be done by the PPP Review Committee and the EAC. The rubric for narrowing the pool is based primarily on:
      • Relevance to the COBRE-NPN research focus
      • Clarity of specific aims and scientific merit
      • Junior Investigator status
      • Proposed COBRE-NPN core utilization
      • Strategic vision for leveraging PPP results into future R-type NIH funding
    • A maximum of eight applicants will be selected. These applicants will be invited to submit a full-proposal, in R01-format, and will then participate in a Shark Tank-type meeting wherein a 10-minute presentation of the proposal is given to the PPP Review Committee who in turn provide the applicant feedback and guidance.
    • Applicants will then submit a revised (A1-like) proposal to be forwarded to the EAC for final evaluation.
    • The EAC will select up to five finalists pending NIGMS approval.
    • Proposals will be prioritized for funding based on scientific merit, thematic research focus, career stage, collaboration teams, and the perceived likelihood of publications and competitive grant applications generated from work.

General Terms and Conditions

General Terms and Conditions of CORE-NPN COBRE Research Pilot Project Program:

    1. COBRE funds will not be released until NIGMS approves the project.
    2. PI or Co-I salary will not be supported. Funds may be used to support purchase of materials and supplies and for laboratory personnel salaries.
    3. At least 30 percent of the funds should be used for services obtained through one or both Cores (Chemistry and DMPK and/or Neuropharmacology Core).
    4. Pilot Project Investigators will be required to deliver a presentation every quarter on their progress.
    5. The investigator will be required to submit at least one abstract for presentation at a national research meeting and to submit one manuscript for peer-reviewed publication acknowledging COBRE and core support, by the end of year 1 of funding.
    6. Recipients will be required to submit an investigator-initiated NIH R01 grant application by the end of the second year of COBRE support. If investigator obtains external support, COBRE support will be discontinued if the COBRE supported project is significantly similar to the newly funded project.
    7. Investigators will be expected to present their research findings to the EAC during their annual review.
    8. The younger scientists, pre-R01 awardee, and assistant professors will be required to identify at least one senior faculty member to serve as their mentor. The more senior scientists at the associate or full professor rank will have the option of selecting a senior mentor to facilitate the development of their project.
    9. Recipients will present their work at the annual Core Research Day.

Prospective applicants with questions about eligibility, program details, application process or requirements are encouraged to contact Dr. Kristie Willett (662-915-6691; kwillett@olemiss.edu).

 

Research Projects

Alberto Jose Del Arco GonzalezDr. Alberto Jose Del Arco Gonzalez

From Stress to Drug Addiction: The Neuronal Networks that Underlie Vulnerability to Drug Abuse

The repeated exposure to stressful experiences makes subjects more vulnerable to develop drug abuse. Vulnerability to drug abuse is associated with the abnormal function of the brain reward system which promotes drug-seeking behavior and enhances the reinforcing effects of drugs (drug sensitization). However, how stress alters the reward system to transform a healthy brain into a vulnerable brain is poorly understood. In preliminary experiments I find that exposing rats to repetitive intermittent social defeat stress (RISD) alters reward-seeking behavior. In line with these findings, previous studies have shown that RISD produces cocaine sensitization and promotes cocaine self-administration. Yet the neuronal networks that explain these behaviors are still unclear. The main goal of this project is to identify the neuronal networks in the brain that lead to abnormal reward-seeking behavior and enhance the effects of drugs during repetitive exposure to stress. Specifically, I will record in vivo neuronal activity in the prefrontal cortex (PFC) and the ventral tegmental area (VTA) since both areas of the brain process rewarding stimuli and regulate the response to stress. 

The central hypothesis of this proposal is that the repetitive exposure to social stress changes how neurons respond to (i.e. encode) reward-seeking cues in the PFC and the VTA. These neuronal changes alter reward-seeking behavior and enhance the reinforcing effects of drugs, making subjects more vulnerable to develop drug addiction. To test this hypothesis:

Specific Aim 1 will determine the neuronal response to reward-seeking cues during social stress. Specific Aim 2 will determine whether cocaine enhances the neuronal response to reward-seeking cues after social stress.

Importantly, this project will take advantage of the Neuropharmacology CORE-NPN to carry out a multilevel experimental design in which  the neuronal activity in the brain after stress is associated with changes in other behavioral and molecular parameters such as motor activity (open field test), rewarding effects (conditioned place preference test), anxiety behavior (plus maze test) and the activity of stress hormones (I.e. corticotropin-releasing factor, corticosterone) in the brain (immunohistochemistry and western blot analysis). Furthermore, the results of this research will help to develop more competitive grant applications to secure NIH R01 funding and promote collaborations between our campus and the Medical School.

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Mohamed Ali IbrahimDr. Mohamed Ali Ibrahim

Mentor: Dr. Samir Ross & Dr. Larry Walker

Novel and Selective CB2 Agonist/Inverse Agonist for Targeting Neurodenerative Disorders

The cannabinoid receptor subtype 2 (CB2) is emerging as a potential target for the development of new therapeutic approaches in several neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). CB2 is expressed by peripheral immune cells and mediates the immunosuppressive effects of cannabinoids and endocannabinoids. Recently, we have developed a new class of selective CB2 ligands as lead compounds for neuroinflammatory and neurodegenerative disorders. Pyrrolo[2,1-c][1,4] benzodiazepines (PBDs) are a class of natural products obtained from various actinomycetes which have both anti-tumor and antibiotic activities. Closer inspection of the newly designed PBD tricyclic skeleton in analogy to the natural CB ligands backbone such as THC and CBN, has sparked an innovative interest in this under explored class of the compounds as a potential source of CB2 selective ligands. We hypothesize that PBD analogs should have the proper configuration that gives the molecules a right-handed twist which will offer the appropriate three-dimensional conformation to fit snugly within the active site of CB receptors, enabling them to interfere with the endocannabinoid signaling system. Interestingly, computational studies and theoretical binding affinities of six selected (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs, have revealed the presence of a selective tight binding attraction towards CB1 and CB2 which have been confirmed via testing. Intriguingly, one of the synthesized compounds showed a selective binding affinity towards CB2 (Ki = 8.4 nM) when compared to CB1 (Ki =65.4 nM). Our finding suggested that introduction of a halogen on the aromatic ring promotes the selectivity of CB2-ligand interaction while introducing a polar side-chain on the aromatic ring escalates the selectivity towards CB1 receptor. This in turn motivates us to move forward with optimizing our scheme for amplifying the selectivity through the generation of twenty four (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs supported by computer-based docking studies and the drug-likeness properties via computational calculation of ADMET and physicochemical properties. The generated ligands will be evaluated for their CB receptor binding and GTP–[35S] assays as well as neuronal viability assessment in CORE-NPN. The most potent analogs will be tested in Alzheimer’s mouse model, J20 (PDGF-APPSw,Ind). The outcome of these studies has the potential to lead to potent therapeutic agents for neurodegenerative diseases and will open the window for future exploratory funding opportunities.


Hoang LeDr. Hoang V. Le

Development of Novel Salvinorin Compounds with 6, 5-fused Rings at C-2

The opioid system plays a crucial role in the modulation of antinociception and a variety of behavioral states like addiction, anxiety, and depression. It is composed of four G-protein coupled receptors: kappa (KOR), mu (MOR), delta (DOR), and nociception (NOR), that are expressed throughout both the peripheral and central nervous system (CNS). Salvinorin A, the main active ingredient in the hallucinogenic plant Salvia divinorum, is one of the most potent, naturally occurring opioid agonists with high selectivity and affinity for KOR. It has the potential to be beneficial in therapy of various CNS disorders. Due to its strong hallucinating effects, salvinorin A has never advanced to clinical trials, but has been used as an important prototype for the development of related drug candidates. Our lab aims to use the Salvinorin scaffold to develop novel compounds to probe the opioid system.


Ahmed OsmanDr. Ahmed M. Osman 

Mentor: Dr. Mahmoud ElSohly & Dr. Mohamed Radwan

Introduction of hydrophilic functionalities into the cannabidiol molecule to ameliorate its lipophilicity for enhancement of its antiepileptic utility

This application is to investigate, primarily, the applicability of singlet oxygen photooxygenation in the introduction of hydrophilic regions in the molecule of cannabidiol (CBD) in order to diminish its excessive lipophilicity. On June 25, 2018, the FDA approved CBD as a treatment for two rare forms of childhood epilepsy, Lennox-Gastaut syndrome and Dravet syndrome. CBD has been reported to possess a wide range of potential therapeutic utilities for several illnesses, including seizure-suppression, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, epilepsy, neuroprotection, depression, as an anxiolytic and as an analgesic. In addition to possessing central effects, CBD exhibits therapeutically beneficial peripheral actions such as anti-inflammatory. Despite the many pharmacological potentials of CBD, its drawbacks have limited its applications in therapeutics. Excessive Lipophilicity has been persistently a major challenge for drug development. The major drawbacks of CBD include: low water solubility, poor absorption, low oral bioavailability (approximately 10%), very high plasma protein binding (>99%), and significant first-pass metabolism. To enhance the absorption and bioavailability of CBD, its excessive lipophilicity should be counteracted by introduction of a hydrophilic region in the CBD molecule. This can be accomplished by Singlet oxygen photooxygenation of CBD. Singlet oxygen photooxygenation, an established reaction, unlike other oxidation methodologies, it results in formation of multiple products with a range of oxygenated/hydroxylated functional groups in a single step. Varying the reaction conditions, including using different photosensitizers, solvents, reaction time, irradiation with UV or incandescent light has resulted in the formation of vicinal diol derivatives, quinones, ethers, and oxides, beside the typical allylic hydroperoxides. The lipophilicity of these products (expressed as logP) will be determined in silico and experimentally, for validation, using HPLC-MS methods. Compounds with logP <5.0, will be advanced for further evaluation. The selected derivatives will be examined for potential affinity to the CB1 receptor, to exclude compounds with psychoactivity. The selected derivatives will be tested in the in vivo Genetic Zebrafish model of epilepsy (Dravet). The second year of the proposed project will be utilized for optimization and scaling up of the selected CBD derivatives, based on the work done in the first year, and will be followed by examination of their antiepileptic effects, utilizing in vivo models. The effect of reducing lipophilicity on the GIT. Permeability will be tested using in vitro models, e.g. the Caco-2 cell assay.


Jason ParisDr. Jason Paris

Mentor: Dr. Marc Kaufman

Natural Neuroendocrine Modulators for HIV-Accelerated Aging

Given the advent of combined antiretroviral therapeutics (cART), the population infected with human immunodeficiency virus type 1 (HIV-1) is aging. In the U.S. alone, nearly 700,000 HIV+ individuals are over the age of 50. Compared to those that are uninfected, these individuals are at risk for an accelerated aging phenotype characterized by sooner transition to the climacteric (post-menopause in women, andropause in men) and predisposition to vasomotor symptoms, cognitive deficits, neuropsychiatric disorder, and age-related frailty (i.e. osteoporosis, muscle weakness, gait/motor aberrations). Symptom burden is typically worse among women compared to men, particularly those reporting amenorrhea vs. those still naturally-cycling.

The mechanisms underlying HIV-accelerated aging are not known and cART does not ameliorate symptomology. We and others have identified the HIV-1 trans-activator of transcription (Tat) protein to be one the most neurotoxic soluble proteins secreted by the virus. Many neurological symptoms may occur downstream of HIV-1 Tat actions, cART does not target Tat, and pregnane steroids (progesterone and allopregnanolone) can ameliorate some Tat-mediated behavioral and CNS pathology. We propose to investigate HIV-accelerated aging in a mouse model of neuroHIV that conditionally-expresses Tat protein. Aged (12-15 mos old) male and female Tat-expressing mice (and their non-Tat-expressing counterparts) will be stratified by endocrine aging status as having maintained reproductive capacity (pre-estropausal) or having transitioned to reproductive senescence (post-estropausal). In Aim 1, mice will be assessed for neuroendocrine measures (pregnenolone and allopregnanolone content) via UPLC/MS, neurocognitive/neuropsychiatric and nociceptive behavior, and indices of frailty. In Aim 2, mice will (or will not) receive a pharmacological enhancer of natural neurosteroids or allopregnanolone and will be assessed for behavior as described in Aim 1, brain morphometry (region gray-matter density, white matter abnormality, and ventricular volume) via MRI, neuronal morphology via Golgi-Kopsch staining, and frailty.

We anticipate HIV-1 Tat exposure to confer vulnerability to an accelerated aging phenotype (particularly in post-estropausal females) and natural neurosteroid enhancement to ameliorate related comorbidities.

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Voucher Program

The purpose of the voucher program is to allow non-COBRE supported University of Mississippi investigators to generate preliminary data for subsequent NIH proposal submissions using the established Natural Products Neuroscience core facilities. The voucher program will provide funds only to support utilization of the services provided by the COBRE-NPN Cores. Application instructions are provided below. Voucher requests may not exceed $5,000/year. Applicants should consult with the appropriate Core directors to ascertain both feasibility of proposed services and projected costs. 

Voucher proposals should be submitted to the COBRE Pilot Project Program Director. The COBRE-NPN Steering Committee (comprising of the Internal Advisory Committee members and Core and Program Directors) will review the applications, using NIH grant guidelines and assign a score that is based on the scientific merit and mission of the Center, and make a decision with respect to funding. Lower priority will be given to past recipients of the voucher program. Funding will be allocated based on recommendations from the committee and availability of funds in the Administrative Core. All voucher recipients will need to provide a short report at the end of the year with respect to the utilization of data obtained in publications, grant applications or other research materials. Support of the COBRE-NPN Cores needs to be acknowledged in all publications that include COBRE generated data.

For additional information, please contact Dr. Soumyajit Majumdar or Dr. Kristie Willett, or call 662-915-7828.

Terms and Conditions

Important: All voucher recipients need to adhere to the following terms and conditions

All Principal Investigators who receive voucher funding must report to the CORE-NPN Pilot Program Director all grant applications (intramural or extramural) that are submitted or awarded based on the services received through the COBRE-NPN cores.

Manuscripts submitted for publication that include work performed using voucher funds must cite the COBRE-NPN grant as follows: “Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under Award Number P30GM122733. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.”

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