It is our long-term goal to understand the mechanism of developmentally programmed capillary regression. As a model system we use the pupillary membrane (PM), a transient capillary network situated in the anterior chamber of the eye. It has the advantage that it is accessible to manipulation through trans- corneal injection, is easily examined in whole-mount when dissected from the eye and regresses postnatally. We have previously shown, (1) that macrophages are required for capillary regression, (2) that macrophages induce programmed cell death in endothelial cells and pericytes to drive capillary regression, and (3) that endothelial cells and pericytes die as a consequence of a macrophage signal received in G1-phase of cell cycle. In the current application, we will pursue the broad question of how macrophages mediate capillary regression with the following aims.
Aim 8 : To determine whether pericytes have a role in regulating PM regression. Pericytes are thought to have a role in maintaining capillaries, perhaps through trophic support. Thus, we will test whether macrophage-induced pericyte death is a distinct and essential step in PM regression.
Aim 9 : To determine whether macrophages influence cell-cycling independent of the induction of apoptosis. Macrophages are a source of endothelial cell mitogens and suppressors of cell-cycle. This raises the possibility that they may regulate endothelial cell- cycle independent of their role in inducing cell death.
Aim 1 0: To determine whether TGFbeta signaling is required for macrophage-induced cell-cycle dependent programmed cell death. TGFbeta can have a pro-apoptotic activity on endothelial cells and is a recognized regulator of cell-cycle. We have shown that there is active TGFbeta in the aqueous that bathes the PM and will determine, using a multiple strategies, whether this is required for PCD or regulation of cell-cycle.
Aim 1 1: To determine whether macrophage-induced PCD is dependent upon the action of matrix proteases. A cell-cycle state dependent cell death suggests that inhibition of essential signaling at the restriction point of cell-cycle may be the cause. We will investigate the possibility that matrix proteases produced by macrophages may cause PCD by degrading essential matrix ligands. There are few systems where the mechanism of capillary regression can be studied in detail. With the methods we have developed and the strategies outlined in this proposal, we have an excellent opportunity to understand this clinically important process. There is every possibility that what we learn about developmentally programmed capillary regression will be applicable to the capillaries that support the growth of tumors or those that are the central feature of some vascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010559-08
Application #
6384397
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Liberman, Ellen S
Project Start
1994-06-01
Project End
2001-09-30
Budget Start
2001-06-01
Budget End
2001-09-30
Support Year
8
Fiscal Year
2001
Total Cost
$218,405
Indirect Cost
Name
New York University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10016
Smith, April N; Miller, Leigh-Anne; Radice, Glenn et al. (2009) Stage-dependent modes of Pax6-Sox2 epistasis regulate lens development and eye morphogenesis. Development 136:2977-85
Cailhier, Jean Francois; Sawatzky, Deborah A; Kipari, Tiina et al. (2006) Resident pleural macrophages are key orchestrators of neutrophil recruitment in pleural inflammation. Am J Respir Crit Care Med 173:540-7
Glass 2nd, Donald A; Bialek, Peter; Ahn, Jong Deok et al. (2005) Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 8:751-64
Cailhier, Jean Francois; Partolina, Marina; Vuthoori, Srilatha et al. (2005) Conditional macrophage ablation demonstrates that resident macrophages initiate acute peritoneal inflammation. J Immunol 174:2336-42
Faber, Sonya C; Robinson, Michael L; Makarenkova, Helen P et al. (2002) Bmp signaling is required for development of primary lens fiber cells. Development 129:3727-37
Lobov, Ivan B; Brooks, Peter C; Lang, Richard A (2002) Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci U S A 99:11205-10
Jung, Steffen; Unutmaz, Derya; Wong, Phillip et al. (2002) In vivo depletion of CD11c(+) dendritic cells abrogates priming of CD8(+) T cells by exogenous cell-associated antigens. Immunity 17:211-20
Faber, S C; Dimanlig, P; Makarenkova, H P et al. (2001) Fgf receptor signaling plays a role in lens induction. Development 128:4425-38
Shirke, S; Faber, S C; Hallem, E et al. (2001) Misexpression of IGF-I in the mouse lens expands the transitional zone and perturbs lens polarization. Mech Dev 101:167-74
Meeson, A P; Argilla, M; Ko, K et al. (1999) VEGF deprivation-induced apoptosis is a component of programmed capillary regression. Development 126:1407-15

Showing the most recent 10 out of 15 publications