The major goal of this grant is the study of the specific immunologic basis of HIV associated dementia (HAD) and linkages between it and other neurodegenerative disorders. This grant brings together in one organizational structure a group of scientists with expertise in areas of neurotoxicology, cellular immunology, neuropathology, neurophysiology, neuropharmacology and molecular biology, who maintain a unified focus on how mononuclear phagocyte biology affects both neurodegeneration and neuroprotection.
The grant consists of three projects supported by four cores:
- Project 1: Mononuclear phagocytes, immunity, and neural progenitor cells
- Project 2: Macrophage-based nanoformulations of anti-retroviral therapy in NeuroAIDS
- Project 3: Macrophage, blood-brain barrier, and modulation of neurodegeneration
- Core A: Cell and Tissue
- Core B: Bioimaging
- Core C: Proteomics
- Core D: Administrative
Publications resulting from this grant.
Project 1: Mononuclear phagocytes, immunity, and neural progenitor cells will
- determine the effects of HIV-1-infected monocyte derived macrophages on human neuronal progenitor cells (NPC) in a murine HIV-1 encephalitis (HIVE) model;
- investigate whether NPC migration is affected by HIV-1 infection and/or immune activation of macrophages and astrocytes and
- define how HIV-1-infected and/or immune-activated macrophages and astrocytes affect NPC proliferation and differentiation through investigation of relevant NPC signaling pathways.
- develop then test anti-retroviral and adjunctive anti-inflammatory nanoparticle (NP) drug formulations for their abilities to effectively enter and be released from human and/or rodent monocyte- and bone marrow-derived macrophages (MDM and BMM);
- test "antibody or ligand coated" NP drug formulations for their abilities to enter and be released from circulating monocytes; and
- text most promising nanoformulation for anti-retroviral efficacy, immune and neuroprotection in rodent models of HIV-1 infection and NeuroAIDS.
- investigate neuroprogenitor cells (NPC) migration across and the functional alterations to the blood-brain barrier (BBB) that occur by neural progenitor cells;
- assess the functional and biological effects of macrophages carrying nanoformulations on the BBB; and
- investigate ability of NPC and NP-loaded macrophages to migrate across the BBB in vivo.
- provide consistent and reproducible primary human white blood cells and murine bone-marrow-derived macrophages;
- obtain human and mouse microglia, astrocytes and/or neurons from brain tissue; and
- provide human brain specimens for the studies of each project and core facility through the department brain bank
- use MRI and SPECT methods for cell tracking and measures of cell distribution kinetics;
- use 1H MRSI, BBB permeability mapping, and arterial spin labeled perfusion mapping to track effects of neurodegenerative diseases and experimental therapies; and
- continue development of advanced image and spectroscopic image processing method.
- provide "state of the art" proteomic and mass spectrometry using 2DE DIGE; ABI4800, MALDI-TOF/TOF; QQ-LIT; iTRAQ; SILAC method;
- develop new analytical techniques for proteomic tests, and
- establish collaborations with experts in bioinformatics to extract new information using four search algorithms ( four search algorithms: MASCOT, Sequest, X!Tandem and ProteinProphe).
Core D: Administrative will
- implement the programmatic goals, scientific policies and procedures of the entire grant to expand, enrich and develop the program, maintain fiscal accountability and resource allocation;
- provide statistical support for all projects