Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Understanding the role of the blood vascular system and endothelial cells in early thymus regeneration after cytotoxic treatments using novel intravital imaging techniques

Award Number: R01HL171971
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2024
PERIOD OF PERFORMANCE END DATE: 07/31/2029

Group Awards By:

View Award Description

Understanding the role of the blood vascular system and endothelial cells in early thymus regeneration after cytotoxic treatments using novel intravital imaging techniques - PROJECT SUMMARY Hematopoietic cell transplantation (HCT) remains an important treatment for hematologic malignancies such as multiple myeloma, lymphoma, acute leukemias, and myelodysplastic syndromes.1 A key component of HCT is the cytotoxic preconditioning required to reduce the burden of malignancy, suppress the host immune system, and enable engraftment and tolerance of the donor hematopoietic cells.2 Unfortunately, conditioning regimens invariably damage the tissues where donor cells engraft and expand (e.g., bone marrow and thymus), leading to significant morbidity and mortality.1 Recent data suggests that radio-resistant thymus vascular endothelial cells (ECs) are critical cells in endogenous thymus regeneration as they provide the conduit for progenitor cell entry into the thymus, express ligands important for early thymic seeding, and secrete regenerative associated factors (RAFs) such as BMP4.3–5 Understanding how the vascular network, and in particular ECs, respond to cytotoxic therapy may give us insights that will enable the development of improved therapies and restoration of adaptive immunity after acute injury.4,5 But how do these regimens change the microenvironment of these tissues (especially the thymus) and impact the recovery of the hematopoietic and adaptive immune systems? To address this question, we need new methods to directly analyze the live thymus in its native site.6 Our previous intravital imaging work demonstrated that cytotoxic therapies drastically change the bone marrow (BM) vascular integrity, oxygen tension (pO2), and cell behavior.7,8 In the thymus, we also observe widespread changes in vascular structure suggesting functional damage. We hypothesize (a) that the native cortical and CMJ vascular compartment is heterogenous with functionally distinct blood vessels; (b) that these distinct vessels are made up of specific sub-types of ECs; (c) that this heterogeneity diminishes as the thymus matures and/or after cytotoxic conditioning; and (d) that cytotoxic conditioning causes abnormal hemodynamics in the blood vascular system leading to spatially and temporally restricted changes in blood flow, vessel permeability, and tissue oxygenation. To test these hypotheses, we propose the following aims: (1) Utilize novel high-resolution intravital imaging and two-photon oxygen microscopy to directly image and functionally characterize the native thymic cortical and CMJ blood vascular physiology; (2) Define EC heterogeneity and subtypes using flow cytometry, single cell RNA sequencing, and immunostaining and identify age dependent functional and anatomical alterations in EC and vascular heterogeneity; and 3) Utilize high-resolution imaging and two-photon phosphorescence oxygen microscopy to characterize the thymus microenvironment over time after myeloablative (MAC) and reduced intensity conditioning (RIC) to identify physiological changes impacting the recruitment of progenitors to the thymus in the context of HCT. The studies outlined in this proposal have the potential to elucidate the microenvironmental effects of cytotoxic preconditioning on the thymus in ways that have not been previously possible through use of novel imaging techniques for direct thymus evaluation.


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: 2025 ( Subtotal = $713,940 )
2025	2025	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Blood Diseases and Resources Research	000	2	7/14/2025	NON-COMPETING CONTINUATION	$713,940
														Subtotal = $713,940

Issue Date FY: 2024 ( Subtotal = $684,794 )
2024	2024	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Blood Diseases and Resources Research	000	1	8/6/2024	NEW	$684,794
														Subtotal = $684,794

Grand Total All Awards = $1,398,734

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Understanding the role of the blood vascular system and endothelial cells in early thymus regeneration after cytotoxic treatments using novel intravital imaging techniques

Award Number: R01HL171971

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2024

PERIOD OF PERFORMANCE END DATE: 07/31/2029

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer