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Enhancing intestinal regeneration with Cysteine mediated dietary intervention

Award Number: K99DK146116
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Enhancing intestinal regeneration with Cysteine mediated dietary intervention - Project Summary/Abstract The small intestine, central to nutrient absorption like amino acids and lipids, houses highly responsive Lgr5+ intestinal stem cells (ISCs) in the crypt bottom. Over the past decade, our group and others have utilized the mouse intestine to investigate how dietary interventions (fasting, high fat diet, mitochondria pyruvate shuttle inhibition, and high cholesterol diet) impact ISC fate decisions. Although much focus has been on ISCs, the small intestine is a complex environment that includes a variety of non-epithelial cells including resident immune cells that coordinate ISC function and maintenance. In particular, tissue-resident immune cells produce and secrete the cytokine interleukin-22 (IL-22), which is known to be a critical regulator of epithelial homeostasis. Amino acids constitute many nutrients in various foods. However, little is known about how specific amino acids impact ISC proliferation and intestinal immune-stem cell interactions. My research has uncovered that the amino acid cysteine controls ISC function through two mechanisms: 1) by directly activating PPAR-CPT1A-HMGCS2 mediated ketogenesis in ISCs via mTORC1 suppression, and 2) by indirectly boosting IL-22 production by CD8β+ T cells through activation of epithelial Coenzyme A (CoA) biosynthesis. The aims of my proposal focus on elucidating both stem cell-intrinsic and extrinsic mechanisms by which cysteine enhances ISC-mediated repair after injury. Specifically, I plan to: 1) determine how cysteine regulates ISC self-renewal and differentiation in intestinal homeostasis and injury through the control of ketogenesis; 2) determine the cysteine metabolic pathways that contributes to ISC mediated repair after injury; 3) determine how CD8β+ T cells mediate the cysteine response in ISC-mediated repair after injury. This career development K99/R00 award will be essential to my training and provide significant support as I transition to an independent investigator. It will protect me to receive the comprehensive education and training through the robust MIT/Harvard system, coupled with the exceptional research resources, fruitful partnerships will uniquely position me to embark on an unparalleled journey as a rising independent investigator in stem cell metabolism research.


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 = $90,000 )
2026	2026	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/19/2026	NEW	$90,000
														Subtotal = $90,000

Grand Total All Awards = $90,000

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Enhancing intestinal regeneration with Cysteine mediated dietary intervention

Award Number: K99DK146116

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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