EVALUATING THE ROLE OF PROTEIN SELF-ASSEMBLY IN THE INNATE IMMUNE SYSTEM - AS HUMANS AGE, LEVELS OF PROINFL…

Assistance award details

Assistance award identifier

ASST_NON_K00AG068511_075

FAIN

K00AG068511

Recipient

NORTHWESTERN UNIVERSITY

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$342,223

Period

Sep 1, 2020 – Dec 31, 2026

Fiscal year

2023

Place of performance state

IL

Source file

FY2023_All_Assistance_Full_20261006.zip

Description

EVALUATING THE ROLE OF PROTEIN SELF-ASSEMBLY IN THE INNATE IMMUNE SYSTEM - AS HUMANS AGE, LEVELS OF PROINFLAMMATORY CYTOKINES INCREASE, LEADING TO A CHRONIC INFLAMMATORY STATE, KNOWN AS INFLAMMAGING. INFLAMMATION IS A HALLMARK OF AGE-RELATED DISEASES AND INCREASES MORTALITY AMONG THE ELDERLY. THE MOLECULAR MECHANISMS THAT UNDERLIE INFLAMMAGING HAVE NOT YET BEEN ELUCIDATED. THEREFORE, THERE IS AN URGENT NEED TO ELUCIDATE THE MOLECULAR MECHANISMS CAUSING PERSISTENT PROINFLAMMATORY SIGNALS, AS DOING SO WILL ACCELERATE EFFORTS TO PREVENT AND TREAT AGE-RELATED AND AUTOINFLAMMATORY DISEASES. THE OVERALL GOAL OF THIS PROPOSAL IS TO DETERMINE IF A SPECIFIC MOLECULAR MECHANISM CONTRIBUTES TO THE PROINFLAMMATORY PHENOTYPE OF AGED MONOCYTES. THE DATA GATHERED SO FAR REVEALS THAT MULTIPLE DEATH DOMAIN PROTEINS THAT FUNCTION AS KEY NODES DOWNSTREAM OF PATHOGEN RECOGNITION RECEPTORS ARE ACTIVATED THROUGH A NUCLEATION-LIMITED ASSEMBLY MECHANISM. THE SELF-SUSTAINING NATURE OF THIS FORM OF ASSEMBLY SHOULD IN PRINCIPLE ALLOW THEM TO PERSIST INDEFINITELY AND CONTINUOUSLY INDUCE MONOCYTES FOR PROINFLAMMATORY SIGNALING. THE PROPOSED AIMS WILL ADDRESS TWO IMPORTANT QUESTIONS: 1) DO PROTEIN SELF-ASSEMBLIES SUFFICE TO ESTABLISH AND MAINTAIN A PROINFLAMMATORY STATE IN MONOCYTES? 2) ARE PROTEIN SELF-ASSEMBLIES INVOLVED IN THE DECLINING PRODUCTION AND FUNCTION OF INNATE IMMUNE CELLS AT THE HEMATOPOIESIS LEVEL? IN THE F99-PHASE OF THIS PROPOSED RESEARCH, THE RESEARCHER AIMS TO IDENTIFY THE MOLECULAR SUBSTRATE THAT DRIVES A PERSISTENT PROINFLAMMATORY STATE IN MONOCYTES. THE IMPLEMENTATION OF NOVEL TOOLS TO MEASURE FUNCTIONALITY OF PROTEIN SELF-ASSEMBLIES IN VIVO, WILL ADDRESS WHETHER THE ASSEMBLED STATES OF CERTAIN DEATH DOMAIN PROTEINS ARE FUNCTIONALLY ESTABLISHING A PROINFLAMMATORY STATE IN MONOCYTES. IN THE K00-PHASE OF THIS PROPOSED RESEARCH, THE RESEARCHER WILL IDENTIFY A POTENTIAL MECHANISM OF HEMATOPOIETIC STEM CELL (HSC) DECAY AND IMPAIRED SELF-RENEWAL CAUSED BY SIGNALOSOME FORMATION. S