REGULATION OF MACROPHAGE APOPTOSIS

Project: Research project

Project Details

Description

Terminal differentiation of macrophage-lineage cells is a critical stage
in determining the functional attributes of mature macrophages. Because
this process occurs after the circulating monocytes enter the tissues, it
is difficult study, and relatively little is known about the regulation of
this important transition. The applicant for this Clinical Investigator
Development Award is a pediatric hematologist 3 years out of fellowship at
Memorial Sloan-Kettering Cancer Center, with a research focus on the
regulation of macrophage differentiation. The applicant's long-term goal
is the development of effective macrophage-based immunotherapy regimens
for the treatment of malignancy. The proposed project is an outgrowth of
the applicant's ongoing studies comparing monocyte-derived macrophages
differentiating in vitro under the control of macrophage colony-
stimulating factor vs. those exposed to the pro-inflammatory cytokine
interferon gamma. The project will examine a novel property which the
applicant has recently identified, activation-induced macrophage
apoptosis, which is regulated during macrophage differentiation by the
interaction of MCSF and IFNgamma. Activation-induced apoptosis is rapid
(6-12 hrs), complete (>90% of cells affected), and occurs only in those
macrophages with a history of exposure to IFNgamma at some point during
differentiation. Its importance may thus be as a physiologic check to
limit uncontrolled activation of inflammatory macrophages. Preliminary
data suggests that the regulatory enzyme protein kinase C (PKC) appears to
play a central role in the signal-transduction pathway linking activation
to cell death in the apoptosis-sensitive macrophages. However, both
sensitive and resistant macrophage subtypes possess abundant PKC activity.
The applicant's hypothesis is that differences must therefore exist either
in the nature of the PKC found in the two types (e.g., due to expression
of different isoenzymes), or in the downstream elements affected by
activation of PKC (in particular the anti-apoptosis proto-oncogene BCL-2).
The specific aims of this proposal are to compare the isoforms,
subcellular localization, and response to activation of PKC in the
apoptosis-sensitive and resistant macrophage subtypes, and to define the
mechanism underlying the rapid decline in BCL-2 expression observed to
occur following activation of the sensitive, but not the resistant,
macrophage subtype. The applicant proposes to take advantage of the
extensive expertise and facilities for the study of protein kinase C and
signal transduction pathways available in the laboratory of Dr. Howard
Rasmussen and colleagues at the applicant's institution. The applicant has
been provided with a fully equipped laboratory by his department
(Pediatrics) to pursue this project, and is being sponsored for this
application by Dr John Hardin, Chairman of Medicine, and co-sponsored by
Dr. Rasmussen. Completion of this project will offer insight into a
previously undescribed aspect of macrophage biology, and will equip the
applicant with sophisticated, state-of-the-art techniques for his long-
term study of macrophage differentiation and activation.
StatusFinished
Effective start/end date7/1/956/30/98

ASJC

  • Medicine(all)