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Characterization of CDKL5 function in host antiviral defense

Award Number: K08AI163377
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 06/18/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Characterization of CDKL5 function in host antiviral defense - Project Summary The goal of this K08 application is to provide a rigorous 5-year scientific and careered development training plan that will facilitate Dr. Josephine Thinwa to transition from a post-doctoral fellow to an independent investigator. The candidate completed her MD/PhD degree at UT Health San Antonio where she focused on innate immunity. After completing internal medicine and infectious diseases training at UT Southwestern, she joined the lab of Dr. Beth Levine, a renowned expert in autophagy, to pursue a project on the interface between autophagy and antiviral immunity. Autophagy is known to function in antiviral innate immunity by specifically targeting intracellular viral components for lysosomal degradation, a process called virophagy. However, how virophagy is activated and regulated is still poorly understood. Based on an unbiased screen for host genes necessary for autophagy induction during infection with two prototypic neurotropic viruses, Sindbis virus (SINV) and Herpes Simplex Virus-1 (HSV-1), her preliminary work identified CDKL5 as a candidate novel regulator of virophagy. She demonstrated that cells deficient in CDKL5 accumulated high levels of SINV capsid protein. Additionally, she determined that CDKL5KO mice were more susceptible to lethal CNS infections with SINV and HSV-1, suggesting that CDKL5 is a critical host antiviral factor. After learning of her mentor’s likely terminal illness, Dr. Thinwa worked with Dr. Levine to establish a mentoring team of accomplished scientists who would provide the expertise and training necessary for her to successfully elucidate the function of CDKL5 in antiviral immunity and become an independent investigator. Her mentorship transitioned smoothly after Dr. Levine passed away to Dr. Michael Shiloh, her primary co-mentor who is a physician scientist and expert in innate immunity and autophagy, and Dr. Julie Pfeiffer, a renowned scientist in viral pathogenesis. They have successfully trained numerous postdoctoral fellows to achieve scientific independence. This mentoring team is perfectly complemented for the proposed studies at the interface between autophagy and antiviral immunity by her outside co-mentor Dr. Hebert “Skip” Virgin. He is a physician scientist and an undisputed leader in the field of autophagy and innate antiviral immunity. He also has a very strong track record of mentoring postdoctoral trainees. A committee of advisors and collaborators consisting of three outstanding scientists will provide additional scientific expertise to enhance her technical skills and offer guidance in scientific and career matters. In her proposed research, the applicant will aim to 1) define the function of CDKL5 in virophagy, 2) delineate which step(s) of the SINV life cycle are modulated by CDKL5, and 3) determine the role of CDKL5 in host antiviral response in vivo. Overall, the proposed studies are likely to expand our understanding of how host cells mitigate the toxic overproduction of viral proteins during infection. Together with access to excellent institutional resources, and training from didactic courses on leadership, grantsmanship and technical skills, she is positioned to become a successful physician- scientist focused on antiviral innate immunity.


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 = $196,560 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	000	5	6/23/2025	NON-COMPETING CONTINUATION	$196,560
														Subtotal = $196,560

Issue Date FY: 2024 ( Subtotal = $196,560 )
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	000	4	5/28/2024	NON-COMPETING CONTINUATION	$196,560
														Subtotal = $196,560

Issue Date FY: 2023 ( Subtotal = $196,560 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	000	3	5/19/2023	NON-COMPETING CONTINUATION	$196,560
														Subtotal = $196,560

Issue Date FY: 2022 ( Subtotal = $196,560 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	000	2	5/31/2022	NON-COMPETING CONTINUATION	$196,560
														Subtotal = $196,560

Issue Date FY: 2021 ( Subtotal = $196,560 )
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	000	1	6/17/2021	NEW	$196,560
														Subtotal = $196,560

Grand Total All Awards = $982,800

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Characterization of CDKL5 function in host antiviral defense

Award Number: K08AI163377

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 06/18/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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