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Molecular Basis of rCGG-Mediated Neurodegeneration

Award Number: R01NS051630
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Molecular Basis of rCGG-Mediated Neurodegeneration - Project Summary: Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects the carriers of premutation alleles (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Common features of FXTAS include progressive intention tremor, gait ataxia, Parkinsonism, and cognitive decline. The neuropathological hallmarks of FXTAS include ubiquitin-positive intranuclear inclusions throughout brain and marked dropout of Purkinje neurons in cerebellum. The long-term goal of this project is to understand the molecular pathogenesis of FXTAS and develop effective therapeutic interventions for FXTAS. At the molecular level, FMR1 CGG premutation carriers exhibit a 2 to 8-fold increase in FMR1 mRNA compared to control individuals. Expression of mutant mRNAs containing long (~100) CGG triplets has been shown to be toxic in cell and animal models. Currently, data support two non-mutually exclusive molecular pathogenesis mechanisms for FXTAS: 1) RNA gain-of-function, in which rCGG repeat-binding proteins (RBPs) become functionally limited through sequestration by lengthy rCGG repeats, and 2) Repeat- associated non-AUG (RAN) translation, whereby translation through the CGG (or antisense CCG) repeats leads to the production of toxic homo-polypeptides, such as FMRpolyG, which in turn interfere with a variety of cellular functions. Our previous work has identified two known RNA-binding proteins, Pur  and hnRNP A2/B1, as RBPs affected by expression of rCGG. We showed that increased expression of either protein could modulate rCGG-mediated toxicity, supporting the RNA-mediated sequestration model of FXTAS. To determine the contributions of both mechanisms to FXTAS pathogenesis, we have generated transgenic lines of mice that express hnRNP A2/B1 and suppress rCGG repeat-mediated toxicity. In parallel, we have taken both whole genome sequencing and global metabolic profiling approaches combined with fly genetic screens to identify potential additional genetic modifiers of FXTAS. We have found that PSMB5 and the sphingolipid metabolic pathway could modulate rCGG repeat toxicity. In this proposal, we plan to further test the hypothesis that FXTAS results from abnormal RNA metabolism stemming from inappropriate association of RBPs with the RNA produced by FMR1 premutation alleles, as well as determine whether these additional candidate modifiers can modulate FXTAS pathogenesis. Successful completion of these studies should significantly advance our understanding the molecular pathogenesis of FXTAS. Identifications of genes and pathways involved in FXTAS will provide valuable targets for future pharmacological research aimed at developing drugs for therapy.


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 = $393,435 )
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	3/16/2023	NON-COMPETING CONTINUATION	$393,435
														Subtotal = $393,435

Issue Date FY: 2022 ( Subtotal = $393,435 )
2022	2022	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	17	3/28/2022	NON-COMPETING CONTINUATION	$39,346
2022	2022	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17	2/3/2022	NON-COMPETING CONTINUATION	$354,089
														Subtotal = $393,435

Issue Date FY: 2021 ( Subtotal = $393,435 )
2021	2021	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	16	2/1/2021	NON-COMPETING CONTINUATION	$393,435
2021	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	12/17/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $393,435

Issue Date FY: 2020 ( Subtotal = $394,256 )
2020	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	15	9/8/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$129,139
2020	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	15	8/6/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$394,256
2020	2019	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	7/28/2020	COMPETING CONTINUATION	$0
2020	2019	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	14	9/8/2020	COMPETING CONTINUATION	-$129,139
2020	2019	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	14	8/5/2020	COMPETING CONTINUATION	$0
														Subtotal = $394,256

Issue Date FY: 2019 ( Subtotal = $657,117 )
2019	2019	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	14	6/7/2019	COMPETING CONTINUATION	$129,139
2019	2019	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	14	7/19/2019	COMPETING CONTINUATION	$0
2019	2019	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	12/14/2018	COMPETING CONTINUATION	$657,117
2019	2018	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	13	6/7/2019	NON-COMPETING CONTINUATION	-$129,139
														Subtotal = $657,117

Issue Date FY: 2018 ( Subtotal = $581,510 )
2018	2018	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	13	5/4/2018	NON-COMPETING CONTINUATION	$58,151
2018	2018	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	1/25/2018	NON-COMPETING CONTINUATION	$523,359
														Subtotal = $581,510

Issue Date FY: 2017 ( Subtotal = $589,688 )
2017	2017	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	12	6/6/2017	NON-COMPETING CONTINUATION	$58,970
2017	2017	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	1/27/2017	NON-COMPETING CONTINUATION	$530,718
														Subtotal = $589,688

Issue Date FY: 2016 ( Subtotal = $597,623 )
2016	2016	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	2/4/2016	NON-COMPETING CONTINUATION	$597,623
														Subtotal = $597,623

Issue Date FY: 2015 ( Subtotal = $605,330 )
2015	2015	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	1/22/2015	NON-COMPETING CONTINUATION	$605,330
														Subtotal = $605,330

Issue Date FY: 2014 ( Subtotal = $626,810 )
2014	2014	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	1/30/2014	COMPETING CONTINUATION	$626,810
														Subtotal = $626,810

Issue Date FY: 2013 ( Subtotal = $702,724 )
2013	2013	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	5/20/2013	NON-COMPETING CONTINUATION	$74,982
2013	2013	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	1/28/2013	NON-COMPETING CONTINUATION	$627,742
														Subtotal = $702,724

Issue Date FY: 2012 ( Subtotal = $759,282 )
2012	2012	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	2/28/2012	NON-COMPETING CONTINUATION	$759,282
														Subtotal = $759,282

Issue Date FY: 2011 ( Subtotal = $905,878 )
2011	2011	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	3/10/2011	SUPPLEMENT FOR EXPANSION	$82,351
2011	2011	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	6	6/24/2011	NON-COMPETING CONTINUATION	$59,892
2011	2011	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	1/27/2011	NON-COMPETING CONTINUATION	$763,634
2011	2011	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	6/22/2011	SUPPLEMENT FOR EXPANSION	$1
														Subtotal = $905,878

Issue Date FY: 2010 ( Subtotal = $837,519 )
2010	2010	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/21/2010	COMPETING CONTINUATION	$753,613
2010	2010	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	2/15/2010	SUPPLEMENT FOR EXPANSION	$83,906
														Subtotal = $837,519

Issue Date FY: 2009 ( Subtotal = $334,267 )
2009	2009	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/19/2008	NON-COMPETING CONTINUATION	$300,841
2009	2009	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	3/27/2009	NON-COMPETING CONTINUATION	$33,426
														Subtotal = $334,267

Issue Date FY: 2008 ( Subtotal = $334,267 )
2008	2008	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/7/2008	NON-COMPETING CONTINUATION	$334,267
														Subtotal = $334,267

Issue Date FY: 2007 ( Subtotal = $334,267 ) (Continued on the next page)
Grand Total All Awards = $9,772,214

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Molecular Basis of rCGG-Mediated Neurodegeneration

Award Number: R01NS051630

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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