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Targeting the regulatory mechanism of hyphae to lateral yeast growth as a novel therapeutic approach against candidiasis

Award Number: R01AI141794
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Targeting the regulatory mechanism of hyphae to lateral yeast growth as a novel therapeutic approach against candidiasis - Abstract A single species Candida albicans, causes half of all invasive fungal infections in humans. The ability of C. albicans to switch reversibly between yeast and hyphe is a major virulence trait that helps it disseminate into the bloodstream (yeast) and invade target organs (filaments). Yeast to hyphae morphogenesis has been extensively studied and its regulation well understood. To the contrary, little is known about the reverse process: hyphae to yeast growth. C. albicans hyphae produce yeast cells from their lateral septal regions, coined as “lateral yeasts”. These lateral yeasts are always found with hyphae at the site of active infection, are the major cells that re- enter the bloodstream and establish distal foci of infection. In fact, lateral yeast cells released from the hyphal layers of biofilm-contaminated catheters have direct access into the bloodstream. We identified the first regulator of hyphae-to-lateral yeast growth, PES1 and have shown that blocking the process (by depleting PES1 in vivo) can abrogate disseminated candidiasis as well as biofilm- associated candidemia. Nothing is known on the regulatory aspects pf PES1. Our preliminary studies show that phosphorylation of Pes1 by Ras-PKA inhibits lateral yeast growth while its dephosphorylation by a Ras- linked phosphatase Yvh1 activates lateral yeast emergence from hyphae and induces biofilm dispersal. Using PES1 as a target for identifying small molecule inhibitors of lateral yeast growth, identified alexidine dihydrochloride that directly inhibited both Pes1 and Yvh1 and protected mice from biofilm-associated disseminated candidiasis. Here, using protein biochemistry assays, we propose to delineate how signaling through Ras-PKA regulates Pes1. We will identify other cognate regulators that interact with Pes1 to control lateral yeast growth, and use this information to discover novel compounds that can interrupt hyphae to lateral yeast growth and disseminated candidiasis. Ultimately, better outcomes for patients with indwelling medical devices is the goal of this application.


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 = -$621 )
2025	2022	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST BLDG MRL	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	4	2/10/2025	NON-COMPETING CONTINUATION	-$621
														Subtotal = -$621

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	4	11/6/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $353,129 )
2022	2022	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	4	8/3/2022	NON-COMPETING CONTINUATION	$353,129
														Subtotal = $353,129

Issue Date FY: 2021 ( Subtotal = $393,191 )
2021	2021	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 WEST CARSON ST.	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	3	7/8/2021	NON-COMPETING CONTINUATION	$393,191
														Subtotal = $393,191

Issue Date FY: 2020 ( Subtotal = $391,471 )
2020	2020	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 WEST CARSON ST.	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	7/13/2020	NON-COMPETING CONTINUATION	$391,471
														Subtotal = $391,471

Issue Date FY: 2019 ( Subtotal = $370,834 )
2019	2019	LOS ANGELES BIOMEDICAL RESEARCH INSTITUTE AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST BLDG N-14	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	8/9/2019	NEW	$370,834
														Subtotal = $370,834

Grand Total All Awards = $1,508,004

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Targeting the regulatory mechanism of hyphae to lateral yeast growth as a novel therapeutic approach against candidiasis

Award Number: R01AI141794

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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