Unraveling the role of trisomy in down syndrome-dependent thymic development

Active Project Grant Awarded Last action

Award ID
F31AI200431
Recipient
Awarding agency
Obligated
$38,554

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 0% complete
Place of performance
Salt Lake City, UT 84112, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
I hypothesize that insufficient positive selection and enhanced negative selection synergistically drive altered thymopoiesis, limiting peripheral immune function among individuals with down syndrome (DS). Individuals with DS experience aberrant peripheral immune responses, including increased infection susceptibility and elevated autoimmune disorder incidence. Peripheral immune dysregulation can be caused by many factors, such as immunity gaps within the T cell compartment. Individuals with DS exhibit defects in the T cell compartment; however, the mechanistic link between chromosome twenty-one (HSA21) triplication and altered thymic development is unknown. To improve T cell-mediated immunity and mitigate immunopathology among this population, IT is necessary to expand our understanding of how thymic development is regulated. This proposal seeks to define a novel role of HSA21-encoded genes in regulating T cell receptor (TCR) signaling during thymic development and determine how trisomy produces altered T cell repertoires among individuals with DS. In aim I, I will determine how trisomy impairs thymopoiesis and positive selection, limiting subset survival in thymi from individuals with DS. I will first assess whether DS-dependent properties confer reduced potential among thymic progenitors by comparing the fate decisions of trisomic thymic progenitors and age-matched controls. Complementary studies will be conducted to quantify DS-dependent perturbations in negative selection pressure and alterations in the TCR repertoire. In aim II, I will investigate how HSA21-encoded genes augment TCR signal transduction in individuals with DS, focusing primarily on the calcium-nfat signaling axis. I will assess if TCR signal transduction is more efficient in thymocytes from individuals with DS by assessing the activation of key signaling proteins following stimulation. Additional studies will determine if RUNX1 overexpression elevates ZAP70 expression, driving enhanced thymic negative selection in individuals with DS. My long-term goal is to gain a deeper understanding of how the molecular regulation of TCR signal transduction shapes fate determination during thymic development, with a particular interest in how HSA21 triplication impacts these processes. Upon completion, I expect these findings to advance the field by informing the development of novel therapeutic programs to bolster T cell development and function, ameliorating immune dysregulation among individuals with DS. Overall, the execution of this proposal will be dually supported by a dedicated CO- mentor team and the group of T cell specialists at the university of utah. This highly collaborative institutional environment will support my growth as a researcher by improving skills in technical prowess, communication, critical thinking, and leadership, ultimately establishing the skillset required to achieve my long-term career goal of leading a successful independent research program focused on T cell development and immunity.

Quick answers

Who received award F31AI200431?

F31AI200431 was awarded to University Of Utah by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on December 7, 2026.

How much is award F31AI200431 worth?

$38,554 has been obligated on F31AI200431.

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