R01AI165563

Intestinal Tissue Intrinsic Mechanisms in Regulation of GI GVHD - The overarching goal of this R01 is to develop non-immunosuppressive strategies to prevent and treat gastrointestinal (GI) GVHD, which remains a major cause of morbidity and mortality from allogeneic hematopoietic cell transplantation (HCT).

We have uncovered an exciting, previously unknown role for metabolic aberrations in allo-reactive T cell target tissues, the intestinal epithelial cells (IECs), in regulating the severity of GI GVHD. Our preliminary data identified a profound defect in mitochondrial complex II (MC II), specifically reduction of its component, succinate dehydrogenase A (SDHA), in IECs that contributed to the severity of GI GVHD. These studies have identified a key role for SDHA in bulk IECs, which is made up of a number of distinct subsets.

Emerging data in recent years suggest that quantitative loss of only a few key IEC subsets, specifically Lgr5+ intestinal stem cells (ISCs), is a critical feature of severe GI GVHD. But the ISC intrinsic pathways that are critical for their function and maintenance remain unknown. Our new preliminary data demonstrate that the mitochondrial metabolic defect, reduction of SDHA component of the mitochondrial complex II (MC II), in the bulk IECs, is observed in the ISC subsets.

In this project, we will build on these exciting and seminal preliminary observations and explore the role of mitochondrial metabolic and bioenergetics functions in the biology of ISCs and its contribution to mitigating the severity of GI GVHD. Specifically, we will test the central hypothesis that host Lgr5+ ISCs cell autonomous deficiency of mitochondrial complex II component, SDHA, amplifies GI GVHD. The specific aims are:

Specific Aim (SA) 1: To determine the functional relevance of mitochondrial complex II component (SDHA) in host Lgr5+ ISCs to GI GVHD.

SA 2: Determine the impact of mitochondrial complex II SDHA deficiency on the biology of Lgr5+ ISC.

If successful, our proposal will provide seminal insights into the fundamental biology of ISCs, provide novel targets to mitigate T cell-mediated target organ damage without adding more immune suppression, and thus have potential implications not only for allo-HCT but also for autoimmunity, solid organ transplantation, and T cell-mediated therapies.

Baylor College Of Medicine

NOT APPLICABLE

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Houston, Texas 770303411 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 417% from $612,086 to $3,165,754.