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Mitochondrial DNA of Normal and Mutant Trypanosomes

Award Number: R01AI014102
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: 09/01/1978
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Mitochondrial DNA of Normal and Mutant Trypanosomes - Abstract We will elucidate how three RNA editing Catalytic Complexes (CCs) interact with Substrate Complexes (SCs), Accessory Factors (AFs), mRNAs and gRNAs to generate translatable mitochondrial mRNAs via precise U insertion and deletion and do so differentially between bloodstream (BF) and procyclic (PF) forms in Trypanosoma brucei. We hypothesize that this occurs via specific molecular interactions between domains of CC, SC and AF proteins and the mRNA/gRNA substrate. We will in: Aim 1. Identify these interactions in PFs and determine which are RNA dependent by a combination of in vivo proximity labelling, protein-protein cross- linking, and affinity purification methods. We will build structural models to identify similarities and differences between the three CCs. Aim 2. Determine the effects of loss of function (LOF) mutations of editing steps on these interactions, interactions with RNA by cross-linking immunoprecipitation and on RNA editing by RT-PCR sequencing. We will prioritize mutations that affect initiation of editing, subsequent catalytic steps and the functions of other essential proteins that are in all three CCs. This will validate and extend results from Aim 1, link the interactions to functional steps of editing and advance the structural models. Aim 3. Identify physical and functional interactions in BF cells by approaches used in Aims 1 and 2 and extended using a MGA knock-in approach which eliminates dependence on RNA editing in BFs and enables additional analyses of LOF mutations and interactions with RNA. This aim will identify similar and different molecular interactions between BFs and PFs. Aim 4. Determine the detailed characteristics of protein domains that function differently between BFs and PFs. We will determine the detailed chemical, structural, and functional characteristics of CC protein domains that affect editing differently in BFs vs. PFs using a focused saturation mutagenesis approach. Overall, this project will advance the understanding of how multiprotein complexes generate translatable mRNAs for essential components of the mt energy generating system in protozoan pathogens and do so differently between their developmental stages. The results may aid identification of targets for novel drug targets that are needed and provide insights into mechanisms of protein/nucleic acid interactions that are widespread and important in eukaryotes and which may lead to practical applications.


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 = $1,158,683 )
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	48	4/25/2025	NON-COMPETING CONTINUATION	$1,158,683
2025	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	46	2/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,158,683

Issue Date FY: 2024 ( Subtotal = $1,131,890 )
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	47	6/14/2024	COMPETING CONTINUATION	$1,021,852
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	47	9/3/2024	COMPETING CONTINUATION	$110,038
														Subtotal = $1,131,890

Issue Date FY: 2022 ( Subtotal = $887,106 )
2022	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	46	4/28/2022	NON-COMPETING CONTINUATION	$887,091
2022	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	41	9/23/2022	COMPETING CONTINUATION	$15
														Subtotal = $887,106

Issue Date FY: 2021 ( Subtotal = $891,798 )
2021	2021	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	45	4/26/2021	NON-COMPETING CONTINUATION	$891,798
														Subtotal = $891,798

Issue Date FY: 2020 ( Subtotal = $896,506 )
2020	2020	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	44	4/16/2020	NON-COMPETING CONTINUATION	$896,506
														Subtotal = $896,506

Issue Date FY: 2019 ( Subtotal = $901,026 )
2019	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	004	43	4/19/2019	NON-COMPETING CONTINUATION	$901,025
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	002	41	1/11/2019	COMPETING CONTINUATION	-$644,623
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	005	41	5/1/2019	COMPETING CONTINUATION	-$4,168
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	006	42	5/1/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$4,168
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	41	11/20/2018	COMPETING CONTINUATION	$4,138
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	003	42	1/11/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$644,624
2019	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	40	11/20/2018	NON-COMPETING CONTINUATION	-$4,138
														Subtotal = $901,026

Issue Date FY: 2018 ( Subtotal = $959,517 )
2018	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	41	5/15/2018	COMPETING CONTINUATION	$959,517
2018	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	40	5/15/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $959,517

Issue Date FY: 2017 ( Subtotal = $876,159 )
2017	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	40	12/21/2016	NON-COMPETING CONTINUATION	$876,159
														Subtotal = $876,159

Issue Date FY: 2016 ( Subtotal = $926,024 )
2016	2016	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	39	12/16/2015	EXTENSION WITH OR WITHOUT FUNDS	$926,024
														Subtotal = $926,024

Issue Date FY: 2015 ( Subtotal = $1,014,278 )
2015	2015	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	38	11/25/2014	NON-COMPETING CONTINUATION	$1,014,278
														Subtotal = $1,014,278

Issue Date FY: 2014 ( Subtotal = $967,512 )
2014	2014	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	37	12/13/2013	NON-COMPETING CONTINUATION	$808,274
2014	2014	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	002	37	6/10/2014	NON-COMPETING CONTINUATION	$89,809
2014	2014	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	37	5/12/2014	SUPPLEMENT FOR EXPANSION	$69,429
														Subtotal = $967,512

Issue Date FY: 2013 ( Subtotal = $824,566 )
2013	2013	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	36	1/10/2013	COMPETING CONTINUATION	$789,476
2013	2013	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	002	36	6/28/2013	COMPETING CONTINUATION	$35,090
2013	2011	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	35	1/10/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $824,566

Issue Date FY: 2011 ( Subtotal = $747,945 )
2011	2011	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	35	6/7/2011	NON-COMPETING CONTINUATION	$747,945
														Subtotal = $747,945

Issue Date FY: 2010 ( Subtotal = $735,994 )
2010	2010	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	34	5/6/2010	NON-COMPETING CONTINUATION	$735,994
														Subtotal = $735,994

Issue Date FY: 2009 ( Subtotal = $728,275 )
2009	2009	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	33	5/26/2009	NON-COMPETING CONTINUATION	$728,275
														Subtotal = $728,275

Issue Date FY: 2008 ( Subtotal = $714,553 )
2008	2008	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	32	4/28/2008	NON-COMPETING CONTINUATION	$714,553
														Subtotal = $714,553

Issue Date FY: 2007 ( Subtotal = $704,834 )
2007	2007	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	31	6/11/2007	COMPETING CONTINUATION	$704,834
														Subtotal = $704,834

Issue Date FY: 2006 ( Subtotal = $993,248 )
2006	2006	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	30	3/15/2006	NON-COMPETING CONTINUATION	$993,248
														Subtotal = $993,248

Grand Total All Awards = $19,731,781

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Mitochondrial DNA of Normal and Mutant Trypanosomes

Award Number: R01AI014102

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: 09/01/1978

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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