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Unraveling the role of trisomy in Down Syndrome-dependent thymic development

Award Number: F31AI200431
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/07/2026
PERIOD OF PERFORMANCE END DATE: 12/06/2027

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Unraveling the role of trisomy in Down Syndrome-dependent thymic development - -Project Summary- 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.


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: 2026 ( Subtotal = $38,554 )
2026	2026	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	000	1	6/9/2026	NEW	$38,554
														Subtotal = $38,554

Grand Total All Awards = $38,554

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Unraveling the role of trisomy in Down Syndrome-dependent thymic development

Award Number: F31AI200431

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/07/2026

PERIOD OF PERFORMANCE END DATE: 12/06/2027

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