: The objectives of this revised application are to define how signals derived from interactions between IL-7 and its receptor promote the development and differentiation of common lymphoid precursors (CLPs) into early B cell precursors. IL-7 signaling is thought to regulate several key aspects of early lymphocyte differentiation, and mutations in the genes encoding IL-7 or its receptor are associated with severe combined immunodeficiency. We will use a variety of approaches to investigate how IL-7 receptor signaling influences CLP differentiation and survival and how these signals guide CLPs to differentiate into B cells versus early dendritic cell precursors. In the course of these studies, we hope to elucidate signaling pathways that are responsible for differentiation versus survival of early lymphocyte progenitors, and uncover the mechanisms by which early lymphoid precursors differentiate into B cells versus dendritic cells. Thus in Aim 1, we will exploit our observation that IL-7 alone promotes CLP differentiation into early B cell precursors to determine whether IL-7 acts to increase CLP survival or induce differentiation.
In Aim 2, we will further exploit this observation by identifying which signaling pathways associated with IL-7 receptor function mediate this effect.
In Aim 3, we will exploit our additional observation that CLPs and a unique subset of early B cell precursors each differentiate into dendritic cells when exposed to the appropriate cytokines. We find that loss of IL-7 receptor expression correlates with the capacity of early B-lineage cells to give rise to dendritic cells, and therefore will investigate whether IL-7 receptor signaling is important for guiding precursor cells away from the dendritic cell lineage and towards the B cell lineage. We will also investigate the possibility that early B-lineage cells constitute a developmental branch point for B and dendritic cell development by employing retroviral marking to identify progeny cells derived from these cells. The basic principles resolved by these studies should have relevance for the mechanisms underlying basic cellular differentiation and transformation, as well as immunodeficiency syndromes resulting from disruptions in cytokine signaling.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052861-02
Application #
6640286
Study Section
Immunobiology Study Section (IMB)
Program Officer
Nasseri, M Faraz
Project Start
2002-06-01
Project End
2007-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
2
Fiscal Year
2003
Total Cost
$356,625
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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