The purpose of the R34 planning grant is to support the effort, conferences, site visits, and other fact-finding processes involved in designing the translational center, Systems Medicine Drug Discovery for Alzheimer's disease. This Center will include Core Facilities charged with providing key technology services and Pathway/Drug-Based Projects that will focus on specific molecular mechanisms and/or predicted pharmacological interventions. Project leaders will be responsible for moving each project (target pathway, drug) through the relevant cores with maximum efficiency. Pathways and projects will undergo continual reassessment of priorities. The goals of the planning period are as follows: (Specific Aim 1) To assemble a team of investigators with appropriate expertise and to develop the most efficient strategy for their productive communication and collaboration;(Specific Aim 2) To develop a plan for generation and exploitation of diverse genetic and omic data collected in humans and various animal models to identify translatable pharmacodynamic biomarkers and enable modeling of drug response determinants in distinct patient populations;(Specific Aim 3) To develop a plan for establishment of multi-scale computational models of pharmacological mechanism, that bridges the divide between cell-level biochemical models and organism-level PK/PD and neuroimaging models;(Specific Aim 4) To plan the most efficient strategy for target validation that will involve conducting quantitative analysis of the effects of small molecules and biologics on therapeutic targets across multiple scales of biological complexity;(Specific Aim 5) To plan the most effective strategy for investigation of the molecular and physiological origins of variability in drug response at the single-cell, organ, and patient level that arises from differences at the level of the proteome, genome and environment;(Specific Aim 6) To develop systems approaches for comprehensive and systematic failure analysis during preclinical and clinical drug development;(Specific Aim 7) To develop the most efficient strategy for rapid and broad sharing of data, analytical and research tools, and models prior to publication;(Specific Aim 8) To ensure open source data enablement and to develop strategies for removing legal/IP barriers to sharing data, biological samples and research tools;(Specific Aim 9) To develop curricula, workshops and seminars for training in systems biology, systems pharmacology, pharmacometrics, PK/PD modeling, omics technologies, translational bioinformatics and other quantitative science areas;(Specific Aim 10) To provide short term training for junior staff and short term sabbaticals for senior team members to expand existing expertise or develop new expertise essential for achieving the programmatic goals of the translational center(s) initiative. Within the planning year, the R34 investigators predict that these Aims will be achieved and that the foundation will have been laid for writing the center proposal.
This R34 planning grant will support the effort, conferences, site visits, and other fact-finding processes involved in designing the translational center, Systems Medicine Drug Discovery for Alzheimer's disease, which will include Core Facilities charged with providing key technology services, and Pathway/Drug-Based Projects focused on specific molecular mechanisms and/or predicted pharmacological interventions. Project leaders will be responsible for moving each project (target pathway, drug) through the relevant cores with maximum efficiency so that the Aims will be achieved and the foundation laid for writing the center proposal.
