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Perturbations of host cell signaling by a complex hepatotropic pathogen

Award Number: R01GM101183
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2013
PERIOD OF PERFORMANCE END DATE: 02/19/2023

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Perturbations of host cell signaling by a complex hepatotropic pathogen - Pathogens must successfully navigate the complex interaction networks of their hosts to survive. During malaria parasite liver stage infection, parasites protect their host hepatocyte by preventing its death and exploiting the host cell resources for growth and development. The host hepatocyte molecular signaling landscape that facilitates successful liver stage replication has not been elucidated, yet it is highly medically relevant. During the first award period of this grant, we have made significant strides towards elucidating a number of signaling pathways upon which the malaria parasite relies and also identified the critical host receptor which parasites engage during entry to establish a permissive environment for intracellular replication and optimal development. We have generated preliminary data that suggests that malaria parasites must not only control conventional forms of host cell defense such as apoptosis, but also must carefully regulate an iron- dependent form of cell death called ferroptosis, which to our knowledge has never before been implicated in host defense against pathogen. This proposal aims to fully delineate the pro-death milieu that the parasite can evade, and what perturbations lead to the demise of the wild-type parasite. We will test the hypothesis that the tumor suppressor P53 is the regulator of ferroptosis in infected cells. We will build on our data which demonstrates that P53 is suppressed by Plasmodium infection, and increasing P53 levels can eliminate liver stage parasites. Finally, we will build on our recent discovery that parasites select a subset of hepatocytes for infection and determine the impact of this selection on establishing optimal host conditions for parasite survival. Throughout the proposed experiments, we will monitor hepatocyte signals not only in response to rodent malaria infection, but also in response to the most deadly human malaria parasite, Plasmodium falciparum, in part by using hepatocytes from a mouse with a humanized liver. The proposed studies will lead to a more comprehensive understanding of the hepatocyte signaling landscape that regulates the success or demise of the Plasmodium liver stage. Accomplishing our aims opens the possibility of altering key host factors with small-molecules that could prevent a wild-type parasite from progressing to symptomatic erythrocyte infection. Such a host-based approach for prophylaxis is novel and will circumvent the massive problem of continuously developing resistance to standard antimalarial drugs. This approach is further fostered by the fact that many hepatocyte proteins are already targets of known therapeutic inhibitors. A more detailed understanding of the complex perturbations elicited by this important intracellular pathogen might also reveal new aspects of hepatocyte signaling.


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 = $0 )
2024	2021	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Biomedical Research and Research Training	000	10	1/8/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Biomedical Research and Research Training	000	10	2/10/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $411,599 )
2021	2021	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Biomedical Research and Research Training	000	10	3/29/2021	NON-COMPETING CONTINUATION	$411,599
														Subtotal = $411,599

Issue Date FY: 2020 ( Subtotal = $411,599 )
2020	2020	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Biomedical Research and Research Training	000	9	3/12/2020	NON-COMPETING CONTINUATION	$411,599
														Subtotal = $411,599

Issue Date FY: 2019 ( Subtotal = $411,599 )
2019	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Biomedical Research and Research Training	002	8	3/19/2019	NON-COMPETING CONTINUATION	$411,599
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Biomedical Research and Research Training	001	7	2/15/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$218,724
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Biomedical Research and Research Training	004	7	5/13/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$6,822
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Biomedical Research and Research Training	003	6	5/13/2019	NON-COMPETING CONTINUATION	-$6,822
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Biomedical Research and Research Training	000	6	2/14/2019	NON-COMPETING CONTINUATION	-$218,724
														Subtotal = $411,599

Issue Date FY: 2018 ( Subtotal = $411,600 )
2018	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Biomedical Research and Research Training	001	6	6/6/2018	NON-COMPETING CONTINUATION	$41,160
2018	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Biomedical Research and Research Training	000	6	4/10/2018	NON-COMPETING CONTINUATION	$370,440
2018	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Biomedical Research and Research Training	003	5	6/19/2018	COMPETING CONTINUATION	$20
2018	2016	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Biomedical Research and Research Training	002	4	6/19/2018	EXTENSION WITH OR WITHOUT FUNDS	-$20
														Subtotal = $411,600

Issue Date FY: 2017 ( Subtotal = $411,600 )
2017	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Biomedical Research and Research Training	000	5	3/13/2017	COMPETING CONTINUATION	$397,950
2017	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Biomedical Research and Research Training	001	5	3/20/2017	COMPETING CONTINUATION	$13,650
														Subtotal = $411,600

Issue Date FY: 2016 ( Subtotal = $359,100 )
2016	2016	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Biomedical Research and Research Training	000	4	3/21/2016	EXTENSION WITH OR WITHOUT FUNDS	$359,100
														Subtotal = $359,100

Issue Date FY: 2015 ( Subtotal = $359,100 )
2015	2015	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Biomedical Research and Research Training	000	3	4/1/2015	NON-COMPETING CONTINUATION	$359,100
														Subtotal = $359,100

Issue Date FY: 2014 ( Subtotal = $469,831 )
2014	2014	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Biomedical Research and Research Training	000	1	2/5/2014	SUPPLEMENT FOR EXPANSION	$36,910
2014	2014	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Biomedical Research and Research Training	001	2	3/26/2014	NON-COMPETING CONTINUATION	$432,921
														Subtotal = $469,831

Issue Date FY: 2013 ( Subtotal = $352,201 )
2013	2013	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Biomedical Research and Research Training	000	1	3/28/2013	NEW	$352,201
														Subtotal = $352,201

Grand Total All Awards = $3,598,229

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Perturbations of host cell signaling by a complex hepatotropic pathogen

Award Number: R01GM101183

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2013

PERIOD OF PERFORMANCE END DATE: 02/19/2023

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