PROJECT 3. NIGRAL TARGETING STRATEGIES FOR RESTORATION OF NEURAL FUNCTION Although intrastriatal grafts of embryonic DA neurons survive, send neurites into the host brain, elevate DA levels in the vicinity of the grafts, and restore motor function in parkinsonian MPTP-treated monkeys, the functional benefits in humans have been variable, somewhat limited and sometimes associated with dyskinesia. These limitations may be due to the ectopic placement of grafts in the striatum and the resulting dysregutated release of dopamine. Recent studies have shown the feasibility of grafting embryonic substantia nigra (SN) into the host SN and grafts of embryonic striatum into the striatum, which can be used to promote directed fiber outgrowth from DA-containing neurites towards appropriate targets. The experiments proposed build upon this knowledge. The hypothesis is that co-grafting embryonic striatum into the striatum and ventral mesencephalic tissue adjacent to the substantia nigra will improve recovery, since replacement nigral cells can be regulated in the nigra and provide appropriate release of dopamine in the normal target areas. Behavioral measures will assess functional recovery, immunohistochemical markers for DA neurons will be used as indices of graft survival in the target regions, and biochemical effects will be determined. Confocal and electron microscopy will aid the depiction of circuit reconstruction that may result from co-grafts. Prior to sacrifice, the retrograde tracer fluorogold wilt be injected in the caudate or putamen to determine if grafted dopaminergic neurons in the nigra are labeled. Using the same outcome measures encapsulated GDNF-producing cells will be implanted strategically to attract appropriate outgrowth in another experiment. Some monkeys will be studied for three years to allow for more complete restoration, determine extent of recovery, and possible side effects, such as dyskinesia. Together, these experiments will measure the degree of functional recovery attained through the placement of DA-specific grafts, subject to proper regulatory influences, into more physiological sites. Results from these experiments will be compared with behavioral, morphological, and biochemical data generated from Projects 1 & 2, as well as with prior transplants done under similar conditions in St. Kitts green monkeys.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
1P01NS044281-01A1
Application #
6824647
Study Section
Special Emphasis Panel (ZNS1-SRB-E (02))
Project Start
2003-09-30
Project End
2008-06-30
Budget Start
2003-09-30
Budget End
2004-06-30
Support Year
1
Fiscal Year
2003
Total Cost
$306,565
Indirect Cost
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Redmond Jr, D Eugene; Evans, Lawrence (2012) Determination of fetal age by ultrasonography in St. Kitts green monkeys. Am J Primatol 74:433-41
Redmond Jr, D Eugene (2012) Using monkeys to understand and cure Parkinson disease. Hastings Cent Rep Suppl:S7-S11
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Bloch, Jocelyne; Kaeser, Mélanie; Sadeghi, Yalda et al. (2011) Doublecortin-positive cells in the adult primate cerebral cortex and possible role in brain plasticity and development. J Comp Neurol 519:775-89
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Redmond Jr, Donald Eugene; Weiss, Stephanie; Elsworth, John D et al. (2010) Cellular repair in the parkinsonian nonhuman primate brain. Rejuvenation Res 13:188-94
Markakis, Eleni A; Vives, Kenneth P; Bober, Jeremy et al. (2010) Comparative transduction efficiency of AAV vector serotypes 1-6 in the substantia nigra and striatum of the primate brain. Mol Ther 18:588-93

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