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Mechanisms of Prion Aggregation

Award Number: R01NS069566
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2011
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Mechanisms of Prion Aggregation - Prion diseases are relentlessly progressive neurodegenerative disorders with death often within six months of the onset of neurologic symptoms. Pathologic features include widespread extracellular prion aggregates, spongiform degeneration, synaptic and neuronal loss, and severe astrogliosis and microgliosis. The structural determinants of the prion protein (PrP) and endogenous co-factors that drive aggregation, govern prion assembly, and impact aggregate spread through the central nervous system are unclear. A major goal of this application is to define when and how the endogenous co-factor, heparan sulfate (HS), promotes fibril assembly in the parenchyma and blood vessels and slows PrP clearance through the interstitial fluid using in vitro and in vivo model systems. We have previously pursued a range of approaches using cell-based prion conversion assays and newly generated transgenic and knock-in mouse models in collaboration with structural biologists to define the mechanisms that underlie PrP self-assembly and species barriers to prion conversion. We discovered using knock-in mouse models that N-linked glycans on PrP reduce spongiform degeneration, hinder plaque formation, and repel HS binding. Further, we found that plaque-forming prions were composed of poorly glycosylated, GPI-anchorless PrP bound to highly sulfated HS, underscoring the pivotal role of PrP post- translational modifications in driving the aggregate conformation and disease phenotype. We also found that reducing HS chain length decreases parenchymal plaque formation and prolongs survival. Finally, we identified highly amyloidogenic segments in the PrP sequence that control cross species prion conversion, as the number and location of glutamine and asparagine residues in PrP raise or lower the prion transmission barrier. In this renewal, we aim to determine the PrP-HS interactions that promote prion aggregate assembly and accelerate disease. We build on our long-standing observation that structural features of PrP, together with host glycosaminoglycans, drive efficient prion conversion. First, we will genetically manipulate neuronal, astrocytic, and endothelial HS chains and determine the impact on prion cell targets and survival using mouse models. Second, we will define how endogenous HS regulates PrP clearance through the interstitial fluid using conditional HS mouse models and radiolabeled PrP. Third, we will test the efficacy of antisense oligonucleotides (ASOs) targeting HS biosynthetic enzymes or Prnp mRNA in the early and mid-stages of prion plaque development in a prion disease model. We expect these mechanistic studies will (i) define how an endogenous co-factor, HS, accelerates and modifies prion disease, and (ii) determine whether reducing PrP interactions with this potential therapeutic target blocks prion spread.


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: 2024 ( Subtotal = $480,834 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	5/23/2024	NON-COMPETING CONTINUATION	$480,834
														Subtotal = $480,834

Issue Date FY: 2023 ( Subtotal = $480,718 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	4/28/2023	NON-COMPETING CONTINUATION	$480,718
														Subtotal = $480,718

Issue Date FY: 2022 ( Subtotal = $501,557 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	12	5/23/2022	NON-COMPETING CONTINUATION	$501,557
2022	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	12/7/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $501,557

Issue Date FY: 2021 ( Subtotal = $501,375 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	5/19/2021	COMPETING CONTINUATION	$501,375
														Subtotal = $501,375

Issue Date FY: 2020 ( Subtotal = $339,063 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	7/9/2020	NON-COMPETING CONTINUATION	$339,063
														Subtotal = $339,063

Issue Date FY: 2019 ( Subtotal = $339,063 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	6/7/2019	NON-COMPETING CONTINUATION	$339,063
														Subtotal = $339,063

Issue Date FY: 2018 ( Subtotal = $339,063 )
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	5/28/2018	NON-COMPETING CONTINUATION	$339,063
														Subtotal = $339,063

Issue Date FY: 2017 ( Subtotal = $339,063 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	6/19/2017	NON-COMPETING CONTINUATION	$339,063
2017	2016	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	5/26/2017	COMPETING CONTINUATION	$142,962
2017	2015	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/26/2017	NON-COMPETING CONTINUATION	-$142,962
														Subtotal = $339,063

Issue Date FY: 2016 ( Subtotal = $339,063 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	6/24/2016	COMPETING CONTINUATION	$339,063
2016	2015	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/22/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $339,063

Issue Date FY: 2015 ( Subtotal = $304,172 )
2015	2015	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/12/2015	NON-COMPETING CONTINUATION	$304,172
														Subtotal = $304,172

Issue Date FY: 2014 ( Subtotal = $301,130 )
2014	2014	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/7/2014	NON-COMPETING CONTINUATION	$301,130
														Subtotal = $301,130

Issue Date FY: 2013 ( Subtotal = $294,233 )
2013	2013	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/19/2013	NON-COMPETING CONTINUATION	$274,414
2013	2013	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	5/20/2013	NON-COMPETING CONTINUATION	$19,819
														Subtotal = $294,233

Issue Date FY: 2012 ( Subtotal = $304,887 )
2012	2012	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/10/2012	NON-COMPETING CONTINUATION	$304,887
														Subtotal = $304,887

Issue Date FY: 2011 ( Subtotal = $316,792 )
2011	2011	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/11/2011	NEW	$316,792
														Subtotal = $316,792

Grand Total All Awards = $5,181,013

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Mechanisms of Prion Aggregation

Award Number: R01NS069566

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2011

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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