Elucidating and harnessing the molecular mechanisms of protective clearance in endogenous and engineered phagocytes - Project Summary/Abstract
Protective clearance describes the process of the removal of membrane-intact cells or parts of cells
without induction of pro-inflammatory responses; it is a central mode of normal development and
homeostasis across tissues and phyla. Executing this process in a regulated and anti-inflammatory
fashion requires exquisite orchestration of a collection of activities including receptor-mediated
phagocytosis, lysosome formation, and intracellular degradation. Protective clearance plays a particularly
important role in maintaining function and homeostasis in the central nervous system (CNS). The
lysosomal storage disorders are a broad family of diseases characterized by dysregulated protective
clearance in the CNS. Batten disease is a class of 13 fatal neurodegenerative lysosomal storage
disorders that usually appear in childhood and comprise the most common inherited pediatric
neurodegenerative disease worldwide. The pathology of Batten disease is linked to synaptic dysfunction
and auto antibody deposition in the CNS. All genetically mapped forms of the disease are monogenic,
caused by mutations in one of 13 ceroid lipofuscinosis (cln) genes. Despite the success mapping the cln
genes, the cell biological mechanisms governing the CLN proteins in space and time remain an open
problem. Further understanding of the fundamental mechanisms underlying CLN protein function may
identify new avenues to treat Batten disease. The goal of this proposal is to elucidate the molecular and
cellular mechanisms underlying protective clearance in endogenous phagocytes and engineer the
process in for therapy by programming phagocytes to eliminate auto antigen-antibody complexes in the
CNS in an anti-inflammatory manner. This project will use three powerful model systems comprised of
living phagocytes and defined targets to define the molecular and cellular mechanisms underlying
protective clearance. In Aim 1, we will use a simplified cell model of protective clearance to explore a
connection we recently discovered between a CLN protein and a conserved phagocyte receptor. In Aim 2,
we will use a novel model of endogenous protective clearance in the retina to systematically define the
functions of each CLN protein during protective clearance. In Aim 3, we will use our expertise in immune
cell programming to engineer phagocytes that eliminate antigen-antibody complexes from the CNS via
protective clearance and test these molecules in vivo in an advanced mouse CNS macrophage transplant
model. Completion of these aims will clarify molecular mechanisms underlying protective clearance,
define how Batten disease mutations dysregulate the process, and investigate the therapeutic potential of
synthetic receptors to eliminate antigen-antibody complexes from the CNS in an anti-inflammatory
manner.
