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Glial uptake of dopamine after L-DOPA medication

Award Number: SC2GM111149
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2016
PERIOD OF PERFORMANCE END DATE: 04/30/2021

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Glial uptake of dopamine after L-DOPA medication - DESCRIPTION (provided by applicant): Parkinson's disease (PD) affects more than a million persons in the U.S. and is the 2nd most common progressive, neurodegenerative disease. Early on, the movement deficits (tremor, rigidity, slowed movement, altered gait), usually respond to oral levodopa (L-DOPA) and other medications. However, with disease progression, L-DOPA's effectiveness gradually diminishes and dyskinesia and motor fluctuations emerge. Most symptoms of PD are due to a reduction of dopamine (DA)-secreting cells in the substantia nigra. In PD, L-DOPA restores function by replacing lost DA. Endogenous L-DOPA and DA concentrations are largely regulated by astrocytes, which maintain extracellular homeostasis. Although astrocytes have several transporter systems for monoamine uptake, including DA, we have shown that astrocytes take up excess of DA via low-affinity, high-capacity Uptake2 transporters. We also demonstrated that astrocytes wrapping around blood vessels take up L-DOPA and contain monoamine oxidase (MAO) type B which oxidizes DA taken up by the cell. We hypothesize that astrocytes take up and oxidize the vast majority of DA converted from L-DOPA, especially when DA neurons are severely degenerated due to PD. Reducing the ability of astrocytes to take up DA through use of specific transporter blockers may permit the use of lower doses of L-DOPA, thereby diminishing DA pulsatility and motor fluctuations. This hypothesis will be tested here in 3 Aims. Aim 1. Identify the specific transporter molecules involved in dopamine reuptake by astrocytes using brain slice and cell culture models. Aim 2. Identify which specific transporter blockers can slow DA reuptake using an astrocyte brain slice model. Aim 3. Identify which Uptake2 blockers are effective in reducing therapeutic L-DOPA concentrations in a whole animal model of PD. The results will greatly enhance the understanding of the role of astrocytes in PD etiology and pave the way to the development of preventive measures for L-DOPA-induced dyskinesia.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = -$2 )
2023	2018	UNIVERSIDAD CENTRAL DEL CARIBE, INC.	100 AVE LAUREL LOMAS VERDES	BAYAMON	PR	00956	BAYAMON	USA	Biomedical Research and Research Training	000	3	11/21/2022	NON-COMPETING CONTINUATION	-$2
														Subtotal = -$2

Issue Date FY: 2021 ( Subtotal = -$34,608 )
2021	2019	UNIVERSIDAD CENTRAL DEL CARIBE, INC.	100 AVE LAUREL LOMAS VERDES	BAYAMON	PR	00956	BAYAMON	USA	Extramural Research Restoration Program: Hurricanes Harvey, Maria, and Irma – non-construction	001	3	9/5/2021	SUPPLEMENT FOR EXPANSION	-$858
2021	2018	UNIVERSIDAD CENTRAL DEL CARIBE, INC.	100 AVE LAUREL LOMAS VERDES	BAYAMON	PR	00956	BAYAMON	USA	Biomedical Research and Research Training	000	3	9/5/2021	NON-COMPETING CONTINUATION	-$33,750
														Subtotal = -$34,608

Issue Date FY: 2019 ( Subtotal = $138,174 )
2019	2019	UNIVERSIDAD CENTRAL DEL CARIBE INC	AVE LAUREL URB SANTA JUANITA	BAYAMON	PR	00956	BAYAMON	USA	Extramural Research Restoration Program: Hurricanes Harvey, Maria, and Irma – non-construction	001	3	4/29/2019	SUPPLEMENT FOR EXPANSION	$138,174
2019	2018	UNIVERSIDAD CENTRAL DEL CARIBE INC	AVE LAUREL URB SANTA JUANITA	BAYAMON	PR	00956	BAYAMON	USA	Biomedical Research and Research Training	000	3	4/26/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $138,174

Issue Date FY: 2018 ( Subtotal = $138,174 )
2018	2018	UNIVERSIDAD CENTRAL DEL CARIBE INC	AVE LAUREL URB SANTA JUANITA	BAYAMON	PR	00956	BAYAMON	USA	Biomedical Research and Research Training	000	3	3/21/2018	NON-COMPETING CONTINUATION	$124,356
2018	2018	UNIVERSIDAD CENTRAL DEL CARIBE INC	AVE LAUREL URB SANTA JUANITA	BAYAMON	PR	00956	BAYAMON	USA	Biomedical Research and Research Training	001	3	5/11/2018	NON-COMPETING CONTINUATION	$13,818
														Subtotal = $138,174

Issue Date FY: 2017 ( Subtotal = $138,174 )
2017	2017	UNIVERSIDAD CENTRAL DEL CARIBE INC	AVE LAUREL URB SANTA JUANITA	BAYAMON	PR	00956	BAYAMON	USA	Biomedical Research and Research Training	000	2	4/24/2017	NON-COMPETING CONTINUATION	$124,356
2017	2017	UNIVERSIDAD CENTRAL DEL CARIBE INC	AVE LAUREL URB SANTA JUANITA	BAYAMON	PR	00956	BAYAMON	USA	Biomedical Research and Research Training	001	2	7/12/2017	NON-COMPETING CONTINUATION	$13,818
														Subtotal = $138,174

Issue Date FY: 2016 ( Subtotal = $140,974 )
2016	2016	UNIVERSIDAD CENTRAL DEL CARIBE ESCUELA DE MED DE CAYEY	POST OFFICE BOX 60-327	BAYAMON	PR			USA	Biomedical Research and Research Training	000	1	4/20/2016	NEW	$140,974
														Subtotal = $140,974

Grand Total All Awards = $520,885

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Glial uptake of dopamine after L-DOPA medication

Award Number: SC2GM111149

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2016

PERIOD OF PERFORMANCE END DATE: 04/30/2021

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