Project Details
Description
PROJECT SUMMARY/ABSTRACT
Enteric neurons (ENs) are required to control gastrointestinal (GI) motility by regulating neurotransmission. Loss
of ENs has been demonstrated in digestive diseases in adults and during aging. In the muscularis propria of the
GI tract, diverse populations of macrophages, called muscularis macrophages (MMs), are linked to the normal
development and maintenance of ENs. While we have shown that MMs closely interact with ENs, the molecules
that may regulate MMs-ENs functional interactions are unknown. Thus, to use MMs as a target for regulating
ENs in digestive diseases, we first need to characterize MMs’ phenotype in humans and identify the mechanisms
regulating MMs-ENs interaction. Our long-term goal is to determine the signaling pathways regulating MMs-ENs
functional interaction and use this knowledge to develop new therapeutic strategies to treat digestive diseases.
In preliminary data generated for this application, we discovered (1) a new population of human MMs closely
associated with nerve fibers. (2) Depletion of this newly discovered MMs population from human organotypic
cultures of small intestine muscularis propria reduces nerve fibers. (3) RNAs from tissues of patients with slow
transit constipation (STC) have reduced expression of Complement 1qa (C1qa), one of the genes enriched in
the newly discovered population of MMs. (4) C1qa, one of the genes enriched in the newly discovered human
MMs population, is exclusively expressed by MMs in mice. (5) Depleting C1qa from MMs reduces synaptic
marker expression, alters GI contractility, and reduces whole gut transit time. (6) Conditional depletion of CSF1
from ENs in a transgenic mouse model induces loss of the newly discovered population of MMs, ENs and
reduces whole gut transit time. Thus, the central hypothesis of this application is that C1qa expressing MMs
regulate GI neurotransmission, and their phenotype depends on CSF1 released from closely associated
ENs. In SA1, we plan to characterize this newly discovered MMs population in STC patients and assess its
contribution to GI contractility using human organotypic cultures. In SA2, we plan to study the contribution of this
novel population of MMs to neurotransmission. In SA3, we propose to study the role of EN-released CSF1 on
circulating monocytes’ recruitment and differentiation into the novel population of MMs. In the long term, we
expect these studies will contribute substantially to creating the basis for targeting MMs as a novel therapeutic
approach to regulate ENs in digestive diseases, such as STC, characterized by loss of ENs.
Status | Active |
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Effective start/end date | 9/1/22 → 6/30/24 |
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases: $399,990.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $400,000.00
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