Projects Paul Coffer

Research in the Lab is concentrated within three (overlapping) research programs:

1. Immunology program
2. Hematooncology program
3. Regenerative medicine program

While primarily fundamental bench-based research, through collaborative ventures with scientists and clinicians within the University Medical Center research, work is directed towards the following goals:
• understanding the molecular basis of childhood diseases
• improving gene, stem cell and cellular therapies
• development of novel therapies for childhood diseases

Immunology Program

The regulation of immune homeostasis requires precise communication between cells of the innate and adaptive immune systems. Dysregulation in components of both types of cellular immunity can lead to a variety of pathological conditions that range from immune deficiencies to chronic activation of the innate immune response.

The "cross-talk" between the adaptive and innate immune systems is mediated by hematopoietic growth and survival factors, commonly termed cytokines. Cytokines direct cells of the immune system through interaction with their cognate receptors on the surface of effector cells. Interaction of ligand and receptor leads to activation of a plethora of intracellular signalling molecules, resulting in the initiation of a complex program of events modifying cellular function. Any imbalance in the levels of these cytokines, or perturbation in receptor-induced intracellular signalling, can have severe consequences for immune homeostasis.

Of particular importance for the tight control of immune function is the presence and role regulatory T cells (Treg) in inflammatory diseases and the interaction between innate and adaptive immunity in guiding tolerance. It is recently become apparent that Treg cells may be crucial targets in the development of novel strategies for the treatment of (auto)immune diseases.

This program applies both a bench-to-bedside and bedside-to-bench approach, which has lead to development and application of experimental disease models (see below).

General aims
1. To understand the cellular and molecular mechanisms controlling the functioning of a normal and productive adaptive and innate immune system.

2. To identify specific (molecular) mechanisms underlying dysregulation of these processes that can lead to both hypo- and hyper-reactive immunity.

3. To develop new technologies to manipulate primary innate immune cells, thereby providing the necessary bridge between fundamental and clinical research.

Hematooncology Program

The production of mature blood cells, hematopoiesis, involves a carefully orchestrated series of events involving self-renewal and differentiation of primitive pluripotent stem cells. This program aims to understand the processes by which normal hematopoiesis becomes dysregulated in the development of bone marrow failure or leukemia.

Although hematopoiesis is controlled at the level of self-renewal, proliferation, survival and differentiation, the specific intracellular signal transduction pathways involved in modulating lineage choices remain largely unsolved. Understanding regulation of these events will allow the development of novel therapeutic strategies for treatment of disease.

Work within this program aims to understand the processes underlying the development of bone marrow failure by combining research focused on regulation of normal hematopoiesis together with a greater understanding of aberrant regulation in HSCs derived from pediatric patients.

General aims
1. Characterization of the molecular mechanisms regulating HSC fate decisions during both normal hematopoiesis and bone marrow failure.

2. To develop and evaluate novel (molecular) therapies for defective bone marrow function at the pre-clinical and clinical phase.

Regenerative Medicine Program

Regenerative Medicine (RM) is directed at the regeneration of mulfunctioning tissues and organs. This program is actively involved in the introduction of novel research lines investigating the therapeutic potential of mesenchymal stem cells (MSC). Pluripotent mesenchymal stem cells (MSCs) are present in a variety of tissues during human development, and in adults they are prevalent in the bone marrow where they have been isolated, expanded in culture and differentiated. They are thought to be the critical in the production of progenitors with the potential to generate a spectrum of tissues including bone, cartilage, fat and the marrow stroma itself.

Our knowledge about the complex, multistep and multifactorial molecular mechanisms underlying MSC differentiation is currently insufficient to generate "tailor-made MSC" for disease-specific application. The potential for the therapeutic use of MSC has been recently investigated in several diverse settings (i) osteogenesis imperfecta; (ii) Hurler syndrome and (iii) graft-versus-host disease.

However, current problems in the use of MSC for regenerative medicine include (a) lack of multipotency after in vitro culture, (b) poor survival of cells when transplanted in vivo, (c) optimal age of donors and source of isolated MSC and (d) poor proliferation of MSC in vitro resulting in minimal expansion.

The recent development of novel reprogramming technologies to generate induced pluripotent stem (iPS) cells has made it possible to generate patient-derived cell lines for studying genotype-phenotype associations, functional genomics, gene therapy and disease modeling in vitro.

This program aims at understanding the molecular and cellular mechanisms underlying the survival, proliferation and differentiation of MSC. By ex-vivo manipulation of these cells it should be possible to increase their therapeutic potential and eventually generate "tailor-made MSCs" for application to specific pediatric diseases. Furthermore the generation of iPS cells from patients provides the opportunity for drug testing and disease modeling. Work currently focuses on generating and modeling bone marrow failure syndromes through iPSC technologies.

General aims
1. To understand the molecular mechanisms regulating the expansion and differentiation of MSC. This involves analysis of the intracellular signaling pathways and epigenetic regulatory mechanisms with the aim of improving the survival, expansion and differentiation of MSC in vivo.

2. To develop novel (molecular) therapies enabling functional modulation of MSC ex-vivo and allowing novel, tailor-made therapeutic strategies for orthopedic, metabolic and immune diseases.

3. To generate and characterize patient-derived iPSC for disease modeling and drug testing.

TOP