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Analysis of C9ORF72-associated poly (GR) interactions on BAF chromatin remodeling complex structure and function

Award Number: K01NS136791
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 12/15/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2029

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Analysis of C9ORF72-associated poly (GR) interactions on BAF chromatin remodeling complex structure and function - Project Summary Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two fatal neurodegenerative diseases. The GGGGCC (G4C2) repeat expansion in the chromosome 9 open reading frame (C9ORF72) constitute the most common form of familial. G4C2 repeat expansions can generate five different dipeptide repeat proteins (DPRs). The arginine containing DPRs, have shown to be highly toxic in several in vitro and in vivo models. We have discovered a novel biochemical interaction between several subunits of the chromatin remodeling complex BRG1/BRM associated factor (BAF) and the DPR poly (GR). This interaction induces the mis-localization and decreased levels of several BAF complex subunits. Our hypothesis is that BAF complex dysregulation will induce changes in BAF complex structure that will concurrently change the chromatin landscape and gene expression profile in neurons leading to neuronal dysfunction and death. In this proposal we will elucidate how of poly (GR)-BAF complex interactions, affect the 3-dimensional structure of BAF complex. The results obtained by cross link mass spectrometry, TurboID analysis, and the chromatin accessibility profile and gene expression analysis will allow us to gain a more comprehensive and in- depth understanding of chromatin dysregulation in the pathogenesis of C9ORF72-related FTD. Dr. Lopez Gonzalez acquired extensive experience in the use of induced pluripotent stem cells to model neurodegenerative disease during his training as graduate student and postdoctoral training. Dr. Lopez Gonzalez joined the Department of Neurosciences at the Lerner Research Institute (LRI) of the Cleveland Clinic in August 2020. To perform his career development and experimental training, he will devote 75% of his time to research under this k01 award. He will be trained in state of the art biochemical and epigenetic techniques. The career development training include 1) attending to career development workshops organized by the LRI, 2) seminars and journal club organization 3) responsible conduct of research courses and 4) presentations in national and international conferences. To establish a strong research program and prepare for competitive NIH funding, Dr. Lopez Gonzalez will be mentored by Dr. Paul Fox. Staff, Cardiovascular and Metabolic Sciences Department and Robert Canova Endowed chair in Inflammation Research Lerner Research Institute, Cleveland Clinic. Dr. Fox has extensive experience in studies of post-transcriptional mechanisms controlling gene expression and cell function. His co-mentor will be Dr. Thomas Fazzio Professor at the Department of Molecular, Cell and Cancer Biology at the University of Massachusetts Medical School his laboratory has develop several new epigenomic methods. Dr. Lopez Gonzalez will meet with his mentor and co-mentor on a monthly basis to discuss the advances of his project, and to receive guidance with career development.


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: 2026 ( Subtotal = $236,668 )
2026	2026	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/26/2026	NON-COMPETING CONTINUATION	$236,668
														Subtotal = $236,668

Issue Date FY: 2025 ( Subtotal = $236,668 )
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/10/2024	NEW	$236,668
														Subtotal = $236,668

Grand Total All Awards = $473,336

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Analysis of C9ORF72-associated poly (GR) interactions on BAF chromatin remodeling complex structure and function

Award Number: K01NS136791

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 12/15/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2029

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