C. ALBICANS INVASIVE GROWTH - THE HUMAN FUNGAL PATHOGEN C. ALBICANS CAUSES LIFE-THREATENING SYSTEMIC INFECT…

Assistance award details

Assistance award identifier

ASST_NON_R01AI177553_075

FAIN

R01AI177553

Recipient

THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.855

Total obligated

$1,978,056

Period

Jan 17, 2024 – Nov 30, 2028

Fiscal year

2024

Place of performance state

NY

Source file

FY2024_All_Assistance_Full_20261006.zip

Description

C. ALBICANS INVASIVE GROWTH - THE HUMAN FUNGAL PATHOGEN C. ALBICANS CAUSES LIFE-THREATENING SYSTEMIC INFECTIONS AND SEVERE MORBIDITY FROM MUCOSAL INFECTIONS. MORPHOLOGY SWITCHING BETWEEN BUDDING AND FILAMENTOUS GROWTH IS CENTRAL TO C. ALBICANS PATHOGENESIS. THE TRANSITION TO HYPHAL GROWTH MAKES C. ALBICANS A MORE AGGRESSIVE PATHOGEN THAT CAN INFECT A BROAD RANGE OF HOST NICHES BY CROSSING EPITHELIAL AND ENDOTHELIAL BARRIERS AND GROWING INVASIVELY INTO TISSUES. HOWEVER, MOST PREVIOUS RESEARCH HAS FOCUSED ON IDENTIFYING UPSTREAM REGULATORS AND GENES THAT PROMOTE HYPHAL GROWTH IN LIQUID CULTURE, WHICH ARE OFTEN NOT IMPORTANT IN VIVO. THEREFORE, LITTLE IS KNOWN ABOUT THE MECHANISMS THAT DIRECTLY PROMOTE INVASIVE GROWTH OF C. ALBICANS IN THE HOST. TO ADDRESS THIS GAP, A GENETIC SCREEN WAS USED TO IDENTIFY MUTANTS THAT ARE STRONGLY DEFECTIVE IN INVASIVE GROWTH. THE PROPOSED STUDIES WILL FOCUS ON THREE SETS OF THESE MUTANTS THAT REVEALED NEW MECHANISMS THAT ARE CRITICAL FOR INVASION. AIM 1 WILL FOCUS ON MUTANTS THAT IDENTIFIED AN IMPORTANT ROLE FOR ENDOCYTOSIS IN INVASIVE GROWTH IN VITRO AND IN VIVO. THESE STUDIES ARE EXPECTED TO REVEAL WHICH STAGES OF ENDOCYTOSIS ARE IMPORTANT AND HOW THEY PROMOTE PLASMA MEMBRANE ORGANIZATION THAT IS NEEDED FOR INVASIVE GROWTH. AIM 2 WILL FOCUS ON TWO OTHER NEWLY DISCOVERED FUNCTIONS THAT MEDIATE NOVEL MECHANISMS FOR INVASION. ONE NEW FUNCTION IS CARRIED OUT BY PXL1, WHICH IS SIMILAR TO PAXILLIN PROTEINS THAT BIND STRESSED ACTIN FILAMENTS TO MEDIATE MECHANO-SENSING IN MAMMALIAN CELLS. THE PXL1D MUTANT WILL BE INVESTIGATED TO DETERMINE HOW IT PLAYS A ROLE IN SENSING THE SURROUNDING MATRIX AND MEDIATING INVASIVE GROWTH. THE OTHER NEW FUNCTION NEEDED FOR INVASIVE GROWTH INVOLVES PATHWAYS THAT REGULATE TRAFFICKING OF V- SNARES, WHICH ARE NEEDED FOR SECRETION. DEFINING THE ROLE OF THESE TRAFFICKING PATHWAYS WILL BE SIGNIFICANT BECAUSE POLARIZED SECRETION IS FUNDAMENTALLY IMPORTANT FOR HYPHAL GROWTH. THE NEW MECHANISMS WILL BE TESTED IN MOUSE M