The role of SERPINB1 in t cell function and its contribution to human diseases

Active Project Grant Awarded Last action

Award ID
R01AI168210
Recipient
Awarding agency
Obligated
$2,603,822

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 66% complete
Place of performance
Forest Hills, TN 37215, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Primary immunodeficiencies (pids) are a group of monogenic diseases caused by inborn errors of immunity (IEI) that confer risk of severe infection, autoimmunity, and cancer. The genetic and immunological study of IEI is instrumental to understand mechanisms of human immunity and to manage and treat patients with pids. Their study is also important to understand more common diseases associated with genetic variants in the same genes. However, despite the relevance and importance of studying pids from the basic science and clinical points of view, half of the PID patients lack a genetic diagnosis. By studying a patient with a PID of unknown genetic etiology that confers susceptibility to severe mycobacterial disease, we identified a nonsense mutation in SERPINB1. Using a combination of population genetics, biochemistry, and molecular biology, we showed that this is the first case of SERPINB1 complete deficiency ever described. SERPINB1 is an intracellular serine protease suicide inhibitor. Its absence in mice causes uncontrolled intracellular protease activity, leading to neutrophil death and subsequent neutropenia. Interestingly, our patient does not display any neutrophil abnormality, but instead, our in-depth immunological characterization showed a reduction in the frequency of activated t cells and CD4+ memory t cells. Our findings suggest that SERPINB1 has a previously unknown function in t cells and antimycobacterial immunity. Our data also indicates that SERPINB1 orchestrates an intracellular protease-mediated pathway essential for t cell activation and survival. Given our findings, this application will test the hypothesis that SERPINB1 is critical for human t cell activation and, by controlling intracellular protease activity, to human diseases. Capitalizing on the unique opportunity that this patient offers to understand the function of human SERPINB1, we propose three complementary approaches. In aim 1, we will characterize the immunological consequences of SERPINB1 deficiency on t cell activation and CD4+ t cell differentiation. We will also study the transcriptional consequences of SERPINB1 deficiency in t cells. With this, we will uncover a previously unknown function of SERPINB1 in human t cells. In aim 2, we will identify and characterize the pathways orchestrated by SERPINB1 in t cells. The absence of SERPINB1 unleashes the action of intracellular proteases. This rare mechanism of PID will allow for chemical inhibition of these proteases for therapeutic purposes. Furthermore, characterizing the SERPINB1-dependent antimycobacterial mechanisms will lead to the identification of additional IEI in its pathway in patients lacking a genetic diagnosis. In aim 3, we will perform phenome-wide association studies (phewas) to identify associations between genetic variants in the SERPINB1 pathway and additional human diseases. This reverse genetic approach will expand what we will learn from the study of a rare disease to benefit a broader group of patients. Our proposed research has far- reaching clinical and biological implications for understanding SERPINB1 mediated immunity, pids, anti- mycobacterial immunity, and the contribution of the SERPINB1 pathway to human disease.

Transactions

Action Obligated Date
Amendment $646,268
Amendment $646,268
Amendment $646,268
Original award $665,018

Subawards

Subrecipient Amount Awarded
Icahn School Of Medicine At Mount Sinai The role of SERPINB1 in T cell function and its contribution to human diseases $102,464
Icahn School Of Medicine At Mount Sinai $102,465
Icahn School Of Medicine At Mount Sinai $102,464
Icahn School Of Medicine At Mount Sinai $95,291

Quick answers

Who received award R01AI168210?

R01AI168210 was awarded to Vanderbilt University Medical Center by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on July 5, 2023.

How much is award R01AI168210 worth?

$2,603,822 has been obligated on R01AI168210.

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