K08HL181198
Project Grant
Overview
Grant Description
Macrophage polarization and function in GVHD - Project summary / abstract
Graft versus host disease (GVHD) remains the major complication of allogeneic hematopoietic stem cell transplantation (HSCT) and occurs following activation and expansion of alloreactive T cells.
Among the tissues and organs impacted by GVHD, the gastrointestinal (GI) tract is a critical and frequently involved locus of disease.
Clinically, GVHD damages the gastrointestinal (GI) tract in up to 60% of transplant patients, and the presence of GI GVHD often exacerbates GVHD in other target organs.
Improved strategies to eliminate GVHD or decrease its severity are needed.
Within the GI tract, macrophages are a tissue-resident innate immune cell population that are derived from donor monocytes and possess plasticity between proinflammatory and anti-inflammatory phenotypes.
Macrophage survival and proliferation is largely regulated by signaling through the colony stimulating factor 1 receptor (CSF-1R), of which M-CSF and interleukin-34 (IL-34) are the known ligands.
In preliminary data, we have shown that the absence of host IL-34 results in significantly impaired GI epithelial barriers and exacerbated GVHD lethality.
Mechanistically, the absence of host IL-34 led to skewing of donor macrophages towards an inflammatory phenotype.
Our lab further identified that the protection conferred by IL-34 was contingent on apolipoprotein E (APOE) production by donor macrophages.
Based on these preliminary findings, I hypothesize that IL-34 functions as a cytokine rheostat that skews macrophage polarization towards an anti-inflammatory phenotype and thereby prevents pathological damage within the GI tract during GVHD.
In this proposal, I have outlined an approach to define the regulation of IL-34 production in intestinal epithelial cells in GI GVHD, delineate mechanisms by which IL-34 inhibits the emergence of proinflammatory T cells within the colon in GVHD, and define the role of APOE in IL-34 mediated regulation of GI GVHD.
I am firmly committed to an independent academic research career and am strongly supported in my career development and research goals by my mentor, advisors, and the Department of Pediatrics at the Medical College of Wisconsin (MCW).
Institutional support includes 75% protected time for research, dedicated wet-lab bench space, independent office space, and start-up funding for equipment and supplies.
Under the guidance of my primary mentor, William Drobyski, MD, and advisors Xue-Zhong Yu, MD, MS, MBA, Chien-Wei Lin, PhD, Bonnie Dittel, PhD, and Joy Lincoln, PhD, I will advance my skills in cutting-edge single cell analytics techniques and applied bioinformatics with direct application to the specific aims of this proposal.
Completion of my comprehensive training plan will provide me with the skills and experience necessary to become a successful independent investigator with expertise in a novel IL-34, macrophage, and T cell signaling axis that influences allogeneic immune responses in the GI tract during GVHD.
Graft versus host disease (GVHD) remains the major complication of allogeneic hematopoietic stem cell transplantation (HSCT) and occurs following activation and expansion of alloreactive T cells.
Among the tissues and organs impacted by GVHD, the gastrointestinal (GI) tract is a critical and frequently involved locus of disease.
Clinically, GVHD damages the gastrointestinal (GI) tract in up to 60% of transplant patients, and the presence of GI GVHD often exacerbates GVHD in other target organs.
Improved strategies to eliminate GVHD or decrease its severity are needed.
Within the GI tract, macrophages are a tissue-resident innate immune cell population that are derived from donor monocytes and possess plasticity between proinflammatory and anti-inflammatory phenotypes.
Macrophage survival and proliferation is largely regulated by signaling through the colony stimulating factor 1 receptor (CSF-1R), of which M-CSF and interleukin-34 (IL-34) are the known ligands.
In preliminary data, we have shown that the absence of host IL-34 results in significantly impaired GI epithelial barriers and exacerbated GVHD lethality.
Mechanistically, the absence of host IL-34 led to skewing of donor macrophages towards an inflammatory phenotype.
Our lab further identified that the protection conferred by IL-34 was contingent on apolipoprotein E (APOE) production by donor macrophages.
Based on these preliminary findings, I hypothesize that IL-34 functions as a cytokine rheostat that skews macrophage polarization towards an anti-inflammatory phenotype and thereby prevents pathological damage within the GI tract during GVHD.
In this proposal, I have outlined an approach to define the regulation of IL-34 production in intestinal epithelial cells in GI GVHD, delineate mechanisms by which IL-34 inhibits the emergence of proinflammatory T cells within the colon in GVHD, and define the role of APOE in IL-34 mediated regulation of GI GVHD.
I am firmly committed to an independent academic research career and am strongly supported in my career development and research goals by my mentor, advisors, and the Department of Pediatrics at the Medical College of Wisconsin (MCW).
Institutional support includes 75% protected time for research, dedicated wet-lab bench space, independent office space, and start-up funding for equipment and supplies.
Under the guidance of my primary mentor, William Drobyski, MD, and advisors Xue-Zhong Yu, MD, MS, MBA, Chien-Wei Lin, PhD, Bonnie Dittel, PhD, and Joy Lincoln, PhD, I will advance my skills in cutting-edge single cell analytics techniques and applied bioinformatics with direct application to the specific aims of this proposal.
Completion of my comprehensive training plan will provide me with the skills and experience necessary to become a successful independent investigator with expertise in a novel IL-34, macrophage, and T cell signaling axis that influences allogeneic immune responses in the GI tract during GVHD.
Awardee
Funding Goals
THE DIVISION OF BLOOD DISEASES AND RESOURCES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE PATHOPHYSIOLOGY, DIAGNOSIS, TREATMENT, AND PREVENTION OF NON-MALIGNANT BLOOD DISEASES, INCLUDING ANEMIAS, SICKLE CELL DISEASE, THALASSEMIA, LEUKOCYTE BIOLOGY, PRE-MALIGNANT PROCESSES SUCH AS MYELODYSPLASIA AND MYELOPROLIFERATIVE DISORDERS, HEMOPHILIA AND OTHER ABNORMALITIES OF HEMOSTASIS AND THROMBOSIS, AND IMMUNE DYSFUNCTION. FUNDING ENCOMPASSES A BROAD SPECTRUM OF HEMATOLOGIC INQUIRY, RANGING FROM STEM CELL BIOLOGY TO MEDICAL MANAGEMENT OF BLOOD DISEASES AND TO ASSURING THE ADEQUACY AND SAFETY OF THE NATION'S BLOOD SUPPLY. PROGRAMS ALSO SUPPORT THE DEVELOPMENT OF NOVEL CELL-BASED THERAPIES TO BRING THE EXPERTISE OF TRANSFUSION MEDICINE AND STEM CELL TECHNOLOGY TO THE REPAIR AND REGENERATION OF HUMAN TISSUES AND ORGANS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
Milwaukee,
Wisconsin
53226
United States
Geographic Scope
Single Zip Code
The Medical College Of Wisconsin was awarded
Project Grant K08HL181198
worth $151,092
from National Heart Lung and Blood Institute in August 2025 with work to be completed primarily in Milwaukee Wisconsin United States.
The grant
has a duration of 5 years and
was awarded through assistance program 93.837 Cardiovascular Diseases Research.
The Project Grant was awarded through grant opportunity Mentored Clinical Scientist Research Career Development Award (Parent K08 Independent Clinical Trial Not Allowed).
Status
(Ongoing)
Last Modified 7/25/25
Period of Performance
8/1/25
Start Date
7/31/30
End Date
Funding Split
$151.1K
Federal Obligation
$0.0
Non-Federal Obligation
$151.1K
Total Obligated
Activity Timeline
Additional Detail
Award ID FAIN
K08HL181198
SAI Number
K08HL181198-4290915554
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Private Institution Of Higher Education
Awarding Office
75NH00 NIH National Heart, Lung, and Blood Institute
Funding Office
75NH00 NIH National Heart, Lung, and Blood Institute
Awardee UEI
E8VWJXMMUQ67
Awardee CAGE
4B829
Performance District
WI-04
Senators
Tammy Baldwin
Ron Johnson
Ron Johnson
Modified: 7/25/25