Funding Research Period Years 2020-2025
Two cores help ensure success of the Center’s research projects through administrative oversight; education and training; bioactivity and mechanistic studies; behavioral phenotyping; and electrophysiological support. Core A (Administrative, Biostatistics, and Management Core) and Core B (Botanical Core).
Core A: Administrative, Biostatistics, and Management Core
Project 1 integrates Core A to ensure proper statistical analysis and to validate BDPP treatment suppresses a set of parameters associated with BBB function. All statistical analysis and analysis of RNA expression will be integrated in the study design. Core A, led by biostatistician and Co Lead Dr. Li Shen, with support of biostatistician Dr. Molly Estill, evaluate which metabolites are responsible for modulating specific genes in microglia. Not only does this powerful sequencing technique enable us to identify genes in microglia that confer susceptibility to depressive-like symptoms, it can identify new molecular targets through which BDPP metabolites promote resilience to stress. All statistical analysis and analysis of RNA expression will be integrated in the study design, in collaboration with Dr. Li Shen the biostatistician of Core A, to evaluate which metabolites are responsible for modulating specific genes in D2 MSN.
Core B: Botanical Core
Project 2 will operate as follows and will rely upon outcomes provided from project 1, project 1 also will synergize with Core B to ensure product integrity of BDPP prior to administration. We want to develop an understanding of the pharmacokinetic and steady-state properties of BDPP metabolites following a 5-week chronic treatment in healthy volunteers. This will allow for an assessment of the dose-concentration relationship and to establish the necessary concentration in plasma to result in the suppression of IL-6 from peripheral monocytes. In order to assess these pharmacokinetic properties, Project 2 utilizes resources available from Core B, which will be responsible for quantification of botanical metabolites in the plasma. Following assessments for pharmacokinetics and steady-state properties, Project 2 will study the association between BDPP metabolites and circulating IL-6inhealthysubjects, following daily dosing (either a low dose, a medium dose, or a high dose) over a five-week treatment cycle. This objective will involve work with Core A, which will integrate a multiple linear regression model to characterize which metabolite, or combination of metabolites, are responsible for observed reductions in the levels of plasma IL-6.
Research Area Summary
The support provided to the investigators of the Research Projects from the two Scientific Cores is critical for the successful execution of individual Research Projects. The Administrative/Statistical Core A will provide oversight/coordination, in addition to Biostatistical and Educational/Training support, for the BDSRC activities. The Bioanalytical Component of Core B will assess the bioavailability of phenolic metabolites and polyphenols in both humans (Project 2) and rodents (Project 1) following treatment with BDPP. The Bioanalytical Core will also be responsible for assessing the steady-state concentration of BDPP metabolites in plasma following chronic administration in subjects over the course of two distinct timepoints: 1 and 2 months. Work that will establish the bioavailability of metabolites derived from BDPP in humans will address any weakness in our preliminary data.
Funding Research Period Years 2015-2020
The Center for Molecular Integrative Neuroresilience is supported by three Research Cores that are critical for the successful execution of individual research projects. The Administrative/Statistical Core A provides oversight and coordination, in addition to biostatistical and educational training support, for the Center’s activities. The Biosynthetic Component of Core B generates biosynthetic polyphenol botanical metabolites to support all in vitro bioactivity and mechanistic studies of the research projects.
Additionally, the Bioanalytical Component of Core B monitors the bioavailability of polyphenols in genetically modified/gnotobiotic mice carrying select commensal microbes to explore the role of the microbiome in polyphenol bioavailability and eventually, efficacy of treatment conducted by the Research Project. The Bioanalytical Component of Core B will provide critical support by monitoring the bioavailability of specific bioactive polyphenols following treatments. The Behavioral and Electrophysiology Core C will operate by providing behavioral phenotyping and electrophysiological support for all the studies proposed in the research projects, which are fundamental aspects for assessment of efficacy following polyphenol treatments in the experimental animals being tested.
Administrative - Biostatistics/Data Management - Supporting Core A
The purpose of the Administrative-Biostatistics/Data Management Supporting Core A is to coordinate and integrate all activities of the studies in the Botanical Supplement Dietary Research Center (BSDRC) application. This is particularly important for the success of the BDSRC studies because all the research projects and Cores are heavily interdependent, including data sharing across multiple projects, and the future direction of one project is in part contingent on the results of another.
This Core, led by Giulio Maria Pasinetti, MD, PhD, and managed by Susan Gursahai, provides a forum for communication, including a framework for formal, structured interactions between the BDSRC investigators; interactions between participating institutions; management of contractual agreements; and allocation of funds. To achieve the administrative goals, Core A, through the Administrative Tier I Plan component:
- Manages an Internal Steering Committee, whose main goal is to promote integration and coordination among the research projects and Cores of the BDSRC studies.
- Implements a plan to govern research projects and Cores leadership through an Internal Steering Committee.
- Establishes an External Advisory Board, designed to provide oversight and assist the PD/PI and Co-PD/PI in scientific and administrative decisions, as well as with other issues involving financial regulatory oversight.
To facilitate the success of these operations and other management goals of Core A, the Administrative Tier I Plan component will operate through three Work Groups: The Administrative Work Group, the Study Coordination Work Group, and the Outreach Work Group. In addition, Core A includes a Biostatistics/Data Management Tier II Plan component, which operates through two Work Groups: the Biostatistics Work Group and the Data Management Work Group, whose main goals are to facilitate data analysis, storage, and scientific communication.
Bioavailability and Biosynthetic - Scientific Core B
The purpose of Core B, led by Rick Dixon, PhD, and James Simon, PhD, is to directly support the overall goals of the Center to clarify mechanisms that dietary polyphenol botanical supplements may use to promote cognition and psychological resiliency. The Core achieves this goal by providing authentication and quality control of all materials used by individual projects; supporting in vivo bioavailability experiments through profiling of polyphenol metabolites in target tissues; and providing mg levels of key polyphenol metabolites through targeted synthetic and bio-synthetic schemes for mechanistic testing by individual projects. To streamline this effort, Core B is divided into two components--Bioanalytical and Biosynthesis. This structure evolved from the previous Mount Sinai School of Medicine Center of Excellence in Complementary and Alternative Medicine, which investigated grape polyphenols in prevention of Alzheimer’s disease. Both University of North Texas and Rutgers provided key functions in the biosynthesis and bioavailability core. The proven complementary nature of individual investigators within Core B creates a strong synergistic team to support individual projects and collaborative efforts focused on achieving center objectives.
Biobehavioral - Scientific Core C
Core C, led by Jun Wang, PhD, and Ming-Hu Han, PhD, supports the overall goals of the BDSRC by facilitating preclinical behavioral testing and electrophysiology studies. The overall goals of the BDSRC are to define the molecular and cellular mechanisms by which bioactive botanicals may beneficially promote psychological resilience in the context of social defeat, preserve cognitive function in the context of sleep deprivation, and to develop probiotic supplements that optimize the utilization of these specific botanicals, with the final goal to develop bioactive botanicals with defined mechanisms of action for immediate application in humans.
Core C is divided into Behavioral Phenotyping and Electrophysiology components. Dr. Wang directs the Behavioral Phenotyping component and provides all the behavior testing proposed in the BDSRC. The Electrophysiology component, directed by Dr. Han provides critical information concerning how these compounds affect brain synaptic function in nucleus accumbens (NAc) (Research Project 1) and hippocampal formation (Research Project 2).
Core C will also provide toxicology analysis for safety profiles of the tested phenolic compounds. The activity of Core C will be based on the specific goals of individual projects, with the overall objective of correlating the biological effects of phenolic compounds with synaptic activity as well as behavioral phenotypes. Dr. Russo, leader of Project 1, will provide his expertise in mechanisms of neuropsychiatric disorders, such as depression and anxiety.