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Studies in Poxvirus Host Range Genes and Tropism

Award Number: R01AI080607
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: 03/16/2009
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Studies in Poxvirus Host Range Genes and Tropism - In this proposal we will uncover the fundamental mechanisms by which cellular factors of the RNA helicase superfamily and virus encoded host range factors modulate each other’s function, which is key for virus-host interactions, innate immunity, cellular transformation and use of oncolytic viruses for cancer treatment. Myxoma virus (MYXV) is a rabbit specific poxvirus that also exhibits the capacity to infect a wide spectrum of human cancer and transformed cells. MYXV is currently being developed as an oncolytic virotherapeutic to treat various classes of cancer. We have recently reported the identification of members of cellular DEAD-box containing RNA helicases that tightly regulate the tropism of MYXV in human cancer cells. One of our goals is to discover the novel virus-host interactions and dissect the pro- vs anti-viral functions of selected key RNA helicases in human cells. In addition, we discovered that blocking the exportin1-nuclear export pathway not only enhances viral replication but also synergistically promotes killing of human cancer cells without affecting normal human cells. Our goal is to study the in vitro and in vivo impact of this nuclear export pathway in MYXV oncolytic virotherapy. We will continue our effort on understanding the function of two key MYXV host range proteins M029 and M-T5. M029 is a member of the poxvirus E3 family of dsRNA Binding Domain (dsRBD) containing proteins, which modulates the functions of key anti-viral RNA helicases such as DHX9 and PKR in human cancer cells. M-T5 is a member of the ANK family of proteins, and our new preliminary data suggests that M-T5 is required for the enhanced MYXV replication in human cancer cells when nuclear export pathway is inhibited. Thus, our goal is to further understand the host range and immune regulatory functions of M029 and M-T5. Based on our observations we propose to investigate the followings: 1. Elucidate the role of select RNA helicases in MYXV replication and cellular tropism. We propose to investigate the anti-viral and pro-viral functions of key cellular RNA helicases that regulate MYXV tropism in human cancer cells and primary immune cells. 2. Investigate the role of M029 in cellular tropism and innate immune responses. We will dissect the molecular mechanisms by which M029 modulates different cellular pathways in cancer and innate immune cells that depend upon nuclear/cytoplasmic shuttling of host restriction factors. We will identify additional M029 and host interactions and dissect the mechanisms by which the M029 interacting proteins DHX9 and PKR regulate MYXV tropism and oncolysis of human cancer cells. 3. Investigate how combination of nuclear export inhibitor and oncolytic MYXV enhances virus replication, cancer cell killing, and oncolytic virotherapy. We will perform in vitro and in vivo studies to understand the mechanisms how inhibition of nuclear export pathway enhances MYXV replication and oncolytic activity in cancer cell, where MYXV replication is restricted. Additionally, we will investigate the role of MYXV-encoded ANK protein M-T5, which is required for this enhanced virus replication when nuclear export pathway is restricted.


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 = $392,500 )
2025	2025	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Allergy and Infectious Diseases Research	000	16	5/30/2025	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2024 ( Subtotal = $392,500 )
2024	2024	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Allergy and Infectious Diseases Research	000	15	5/7/2024	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2023 ( Subtotal = $392,500 )
2023	2023	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Allergy and Infectious Diseases Research	000	14	5/26/2023	NON-COMPETING CONTINUATION	$392,500
2023	2023	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Allergy and Infectious Diseases Research	001	14	7/20/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $392,500

Issue Date FY: 2022 ( Subtotal = $392,500 )
2022	2022	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Allergy and Infectious Diseases Research	001	13	6/3/2022	NON-COMPETING CONTINUATION	$392,500
2022	2019	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Allergy and Infectious Diseases Research	000	11	10/5/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $392,500

Issue Date FY: 2021 ( Subtotal = $392,500 )
2021	2021	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Allergy and Infectious Diseases Research	000	12	6/23/2021	COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2019 ( Subtotal = $386,250 )
2019	2019	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Allergy and Infectious Diseases Research	000	11	11/15/2018	NON-COMPETING CONTINUATION	$386,250
														Subtotal = $386,250

Issue Date FY: 2018 ( Subtotal = $386,250 )
2018	2018	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Allergy and Infectious Diseases Research	000	10	11/10/2017	NON-COMPETING CONTINUATION	$386,250
														Subtotal = $386,250

Issue Date FY: 2017 ( Subtotal = $311,657 )
2017	2017	UNIVERSITY OF FLORIDA	207 GRINTER HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	8	3/15/2017	NON-COMPETING CONTINUATION	-$375,000
2017	2017	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Allergy and Infectious Diseases Research	002	9	3/15/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$386,250
2017	2017	UNIVERSITY OF FLORIDA	207 GRINTER HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	8	11/23/2016	NON-COMPETING CONTINUATION	$375,000
2017	2017	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Allergy and Infectious Diseases Research	005	9	4/20/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$74,593
2017	2016	UNIVERSITY OF FLORIDA	207 GRINTER HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	004	7	4/20/2017	NON-COMPETING CONTINUATION	-$74,593
2017	2016	UNIVERSITY OF FLORIDA	207 GRINTER HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	003	7	4/4/2017	NON-COMPETING CONTINUATION	-$74,593
														Subtotal = $311,657

Issue Date FY: 2016 ( Subtotal = $375,000 )
2016	2016	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	7	11/20/2015	NON-COMPETING CONTINUATION	$375,000
														Subtotal = $375,000

Issue Date FY: 2015 ( Subtotal = $375,000 )
2015	2015	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	6	11/28/2014	COMPETING CONTINUATION	$375,000
2015	2013	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	5	11/27/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $375,000

Issue Date FY: 2013 ( Subtotal = $331,901 )
2013	2013	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	5	1/18/2013	NON-COMPETING CONTINUATION	$236,480
2013	2013	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	5	1/25/2013	NON-COMPETING CONTINUATION	$81,297
2013	2013	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	002	5	6/6/2013	NON-COMPETING CONTINUATION	$14,124
														Subtotal = $331,901

Issue Date FY: 2012 ( Subtotal = $353,852 )
2012	2012	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	4	2/7/2012	NON-COMPETING CONTINUATION	$353,852
														Subtotal = $353,852

Issue Date FY: 2011 ( Subtotal = $354,519 )
2011	2011	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	3	6/7/2011	NON-COMPETING CONTINUATION	$32,230
2011	2011	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	3	2/22/2011	NON-COMPETING CONTINUATION	$322,289
														Subtotal = $354,519

Issue Date FY: 2010 ( Subtotal = $358,685 )
2010	2010	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	2	2/26/2010	NON-COMPETING CONTINUATION	$358,685
														Subtotal = $358,685

Issue Date FY: 2009 ( Subtotal = $362,822 )
2009	2009	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	1	3/10/2009	NEW	$362,822
														Subtotal = $362,822

Grand Total All Awards = $5,558,436

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Studies in Poxvirus Host Range Genes and Tropism

Award Number: R01AI080607

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: 03/16/2009

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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