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Defining actin-based mechanisms driving basic cell functions and pathogenic behaviors in Naegleria

Award Number: F32AI150057
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/25/2020
PERIOD OF PERFORMANCE END DATE: 08/24/2023

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Defining actin-based mechanisms driving basic cell functions and pathogenic behaviors in Naegleria - Project Summary The “brain-eating amoeba” Naegleria fowleri is an NIAID Priority Category B Pathogen that carries a 95% fatality rate, yet the mechanisms underlying its basic biology and pathogenic behaviors remain largely unstudied. Because understanding the cell biology of Naegleria is critical to the development of therapeutics, my long-term goal is to define the cellular and molecular basis of Naegleria pathogenesis. Unlike human cells, from which Naegleria diverged 1-2 billion years ago, these amoebae do not possess cytoplasmic microtubules. This suggests that the actin cytoskeleton, assembled by the Arp2/3 complex and formin family proteins, is the primary driving force for many cellular processes essential to cell survival and pathogenesis. Therefore, my overall objective in this application is to determine how actin cytoskeletal rearrangements promote cell motility, which is important for establishing infection, contractile vacuole pumping, which is required for surviving osmotic pressure, and cell division, which is critical for robust colonization in the brain. To achieve this objective, I propose the following specific aims: (Aim 1) determine the Arp2/3 complex activators driving cell motility, (Aim 2) define the formin-based mechanisms governing contractile vacuole dynamics, and (Aim 3) identify the actin nucleators and molecular mechanisms responsible for cytokinesis. I will address these aims using orthogonal cellular perturbations (small molecule inhibitors to impair the Arp2/3 complex and formin family proteins, as well as individual gene targeting using morpholinos) and environmental perturbations by changing external osmotic pressure. I will measure phenotypes of single cells in detail with microscopy, and complement this by collecting quantitative data on cell populations with flow cytometry and gene expression assays. Because the cell biology underlying pathogenesis and basic functions in Naegleria is severely understudied, defining how actin orchestrates motility, division, and contractile vacuole dynamics is critical for uncovering drug targets to treat these deadly infections. Completing this project will not only advance the mission of the NIH, but it will also prepare me for a career as an independent investigator at a research-intensive university studying the cell biology of Naegleria. The career development resources available to postdocs and the excellent core facility trainings at UMass create an ideal institutional environment for my training. Further, the mentorship of Dr. Fritz- Laylin, an expert on Naegleria biology, and Dr. Wadsworth, who specializes in cell division, will ensure the success of this project as well as my transition to a career as an independent researcher.


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 = -$6,944 )
2025	2021	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Allergy and Infectious Diseases Research	000	2	10/23/2024	NON-COMPETING CONTINUATION	-$6,944
														Subtotal = -$6,944

Issue Date FY: 2023 ( Subtotal = -$74,434 )
2023	2022	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Allergy and Infectious Diseases Research	000	3	12/8/2022	NON-COMPETING CONTINUATION	-$74,434
														Subtotal = -$74,434

Issue Date FY: 2022 ( Subtotal = $74,434 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Allergy and Infectious Diseases Research	000	3	8/19/2022	NON-COMPETING CONTINUATION	$74,434
														Subtotal = $74,434

Issue Date FY: 2021 ( Subtotal = $70,434 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Allergy and Infectious Diseases Research	000	2	8/24/2021	NON-COMPETING CONTINUATION	$70,434
														Subtotal = $70,434

Issue Date FY: 2020 ( Subtotal = $64,926 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Allergy and Infectious Diseases Research	000	1	2/25/2020	NEW	$64,926
2020	2020	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Allergy and Infectious Diseases Research	002	1	3/12/2020	NEW	$0
2020	2020	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Allergy and Infectious Diseases Research	001	1	3/12/2020	NEW	$0
														Subtotal = $64,926

Grand Total All Awards = $128,416

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Defining actin-based mechanisms driving basic cell functions and pathogenic behaviors in Naegleria

Award Number: F32AI150057

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/25/2020

PERIOD OF PERFORMANCE END DATE: 08/24/2023

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