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Identify 70 bp repeat-associated chromatin components by End-targeting Proteomics of Isolated Chromatin segments (PICh) and initiate their functional characterization

Award Number: R03AI164182
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/04/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Identify 70 bp repeat-associated chromatin components by End-targeting Proteomics of Isolated Chromatin segments (PICh) and initiate their functional characterization - Project Summary Trypanosoma brucei causes human African trypanosomiasis, which is frequently fatal without treatment. Few drugs are available for treating this disease, most of which have severe side-effects and are difficult to administer, while drug-resistant T. brucei infection has been on the rise. In addition, T. brucei also causes animal African trypanosomiasis, which has been a significant economic burden in sub-Sahara Africa. It is therefore important to further study T. brucei pathogenesis and identify better targets for future development of anti-parasite agents. T. brucei regularly switches its major surface antigen, VSG, to evade its mammalian host immune response. VSG switching is a major pathogenesis mechanism that enables T. brucei to establish and maintain a long-term infection. However, how VSG switching is initiated naturally in T. brucei is still not clear. T. brucei has >2,500 VSG genes and pseudogenes, all of which are located at subtelomeres. However, VSGs are expressed exclusively from subtelomeric polycistronic VSG expression sites (ESs). VSG is the last gene in any ES and within 2 kb from the telomere repeats. T. brucei has multiple ESs with very similar sequences, but only one ES is fully active at any time, resulting in a single type of VSG being expressed on the cells surface. DNA recombination has been shown to be a major pathway for VSG switching. Most VSG genes are flanked by two common sequences, which provide sequence homology for recombination between the active and a silent VSG gene in DNA recombination-mediated VSG switching events. First, all VSG 3’UTR has a common 14 nt sequences. Long telomere sequences are also found downstream of ES-linked VSGs and VSGs at minichromosome subtelomeres. Second, upstream of most VSG genes are 70 bp repeats. The 70 bp repeats in ESs can be several kb to several tens kb long. It has been shown that introducing a DNA double strand break in the 70 bp repeats immediately upstream of the active VSG gene increases the VSG switching rate for ~ 250 fold. In addition, DNA breaks are found in the 70 bp repeats in WT cells. Therefore, 70 bp repeat integrity is expected to significantly affect VSG switching frequency. However, it is unknown whether any proteins specifically associate with the 70 bp repeats, even though their sequences are highly conserved, and their associated proteins are expected to help maintain their integrity and to participate in the regulation of VSG switching. In this small project, we aim to use an improved “end-targeting proteomics of isolated chromatin segments” (ePICh) approach to isolate the 70 bp repeat chromatin and identify proteins associated with the 70 bp repeats by mass spectrometry. We will validate candidates identified in the 70 bp repeat ePICh and initiate their functional analysis. Our work will reveal clearly whether any proteins specifically associate with the 70 bp repeats, which will allow us to investigate how 70 bp repeats integrity is maintained. Our findings will open up new avenues for better understanding of the T. brucei pathogenesis and contribute to eradicate this parasite eventually.


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: 2025 ( Subtotal = $0 )
2025	2022	CLEVELAND STATE UNIVERSITY	2121 EUCLID AVE	CLEVELAND	OH	44115	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	2	6/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	CLEVELAND STATE UNIVERSITY	2121 EUCLID AVE	CLEVELAND	OH	44115	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	2	5/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $74,250 )
2022	2022	CLEVELAND STATE UNIVERSITY	2121 EUCLID AVE	CLEVELAND	OH	44115	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	2	5/20/2022	NON-COMPETING CONTINUATION	$74,250
														Subtotal = $74,250

Issue Date FY: 2021 ( Subtotal = $74,250 )
2021	2021	CLEVELAND STATE UNIVERSITY	2121 EUCLID AVE	CLEVELAND	OH	44115	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	1	6/3/2021	NEW	$74,250
														Subtotal = $74,250

Grand Total All Awards = $148,500

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Identify 70 bp repeat-associated chromatin components by End-targeting Proteomics of Isolated Chromatin segments (PICh) and initiate their functional characterization

Award Number: R03AI164182

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/04/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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