There are compelling research opportunities for Parkinson’s disease (PD)
therapeutics. While L-dopa provides an initial relief, there is a need
for alternative strategies to deal with the continued loss of dopaminergic
(DA) neurons, axons and terminals.
The NINDS Udall Parkinson's Disease Research Center of Excellence:
We have a functional collaborative scientific group centered at McLean
Hospital and Harvard Primate Center funded by the NIH/NINDS that investigates
neuroprotective, neuromodulatory and neural transplantation approaches
for PD. We use animal models, including MPTP-treated animals with loss
of dopamine cells, synapses and function. This Center is organized around
3 Cores that serve this and other NIH PD Centers, and 3 specific Projects
that explore the shared theme of “Novel Therapeutic Approaches for Parkinson’s
Project 1. Functional differences between dopamine (DA) neurons
in the substantia nigra (A9) that are vulnerable to PD compared to those
spared in the same midbrain tissue region A10 (VTA) are examined. We discovered
new gene and molecular candidates for neuroprotection by specific laser-capture
and genomic analysis of characteristic DA neurons, now tested systematically
by tissue culture and animal models to identify new pathways and substances
providing insights into the pathogeneses and novel therapies for PD. Project
1 links to NIH Udall Centers, including specific collaborations with Duke
U Udall Center for genomic convergence analysis of PD susceptibility genes
from bioinformatics, linkage analysis and finally functional tests in
our PD model systems.
Project 2. Post-mitotic but immature DA neurons are derived from
primate and human stem cells for restorative transplantation into sophisticated
PD model primates (including functional tests and imaging - see Core B).
Project 2 works with collaborators and NIH Udall Centers, and like Project
1 and 3 is internally served by Core A, B and C, and specifically by its
transplantation in PD primate models linked to the supply of genetically
engineered human stem cells produced in Project 3.
Project 3. Specific midbrain genes and transcription factors controlling
DA neuron development are identified and engineered into mouse and human
stem cells. The resulting DA neurons are tested for functional repair
in PD models in collaborative experiments in the Center. By using combinations
of factors, a large fraction of stem cell derived cultured TH-positive
GFP labeled and midbrain mouse or human neurons are sorted for purity
and safety by the Center’s advanced FACS technology before transplantation.
This PD Center also provides significant PD research education and training
for scientists, and service to the PD patient and medical research communities.
The Center’s 3 research projects and its integrated Administrative
Core (Core A), Functional Imaging Core (Core B) and a Clinical Transplantation,
Bioinformatics, Human and Stem Cell Marker Core (Core C) are unique components
in the NIH Udall Center of Excellence Consortium. The Harvard-McLean NIH
Parkinson's Disease Research Center of Excellence provides a specialized
environment for synergistic PD research on stem cell derived therapies,
novel insights into functional genetic analysis of vulnerability of midbrain
DA neurons and cutting edge research of new modalities leading to novel
treatments for PD patients.