The research performed through this project is very important for the fields of solid organ and bone marrow transplantation because it focuses on a potential new target to increase engraftment of stem cells. Currently, patients that receive stem cell transplants from a non-identical donor must take medications to suppress their immune system; otherwise the stem cells will be rejected.
Stem cell trials have been extended to solid organ transplantation, where it has been shown that kidney transplants can be managed with little or no immunosuppressive medications when stem cells are given to the patient at the time of transplantation. In many cases though the stem cells are rejected and the patient must resume toxic medications.
Our laboratory has been very interested in understanding ways to prevent the rejection of stem cells and has focused on a phylogenetically conserved group of cellular receptors called pattern recognition receptors. This project is focused on understanding how to prevent rejection of stem cells through modifications of these receptors. We hope to identify novel targets to prevent the rejection of stem cells in order to decrease the occurrence of graft versus host disease after bone marrow transplantation and also improve the opportunities for long-term transplant survival without the use of toxic immunosuppressive medications.
The research we will undertake will benefit the State of California and its residents in two major ways. First it promises to define a novel targets to prevent rejection of stem cells that are transplanted into their new host. This is very important because rejection of hematopoietic stem cells is a major impediment to successful efforts at both bone marrow and solid organ transplantation. Patients needed life-saving solid organ transplants and patients that receive bone marrow transplants from donors that are not perfectly matched to them reject their grafts unless they take powerful medications to suppress their immune system. This project is focused on finding a way to help prevent the rejection of these grafts without the need for immunosuppressive medications.
The second way the project will benefit the State of California is to provide new employment opportunities within the State at a large University that conducts biomedical research. This project will not only directly support the employment of three California citizens devoted to biomedical research, but the work it generates will support California-based biomedical science companies, California University personal and other local companies that employ California citizens that produce the reagents and the supplies used in the proposed studies.
This Exploratory Concepts Award proposal is focused on examining how blockade of a family of intracytoplasmic proteins of the innate immune system - called pattern recognition receptors (PRRs) - enhances the engraftment of hematopoietic stem cells (HSCs). It is anticipated that findings from these studies may provide information that could lead to an improvement in the success of solid organ and/or bone marrow transplantation. The PI proposes two aims:  to determine how the PRR-mediated signals influence donor HSCs and  how the stem cells from mice null for the PRR induce host T-cell non-responsiveness to donor antigens, as well as the mechanisms involved.
Novelty and Transformative Potential
- If successful, these studies could provide insight on overcoming the allogeneic barrier to stem cell transplantation, which could be transformative. This could ultimately lead to changing the clinical approach to transplantation (whole organ and bone marrow).
- This proposal will examine a novel hypothesis that examines the role of a novel target (PRRs) in enhanced engraftment of stem cells in the host.
- However, it remains to be determined whether findings generated in genetically altered mouse models are readily translatable to humans. Some reviewers expressed concern that the potential transformative nature of this research is limited by the lack of work in the human system. Others felt the work would be translatable, and this is the logical starting point to investigate the hypothesis.
Feasibility and Experimental Design
-The translational significance of the studies from mouse to human was a source of debate between the reviewers. The lack of any proposed experiments in the human system that would demonstrate the findings in the mouse model system are applicable to human HSC engraftment was the primary criticism of the experimental plan. Some reviewers thought the mouse system has produced translatable results in the past and this was sufficient while others wished the applicant had included some experiments demonstrating the potential impact on engraftment of human HSCs.
- The experimental approach is sound and the experimental plan is well designed to test the hypothesis.
- The preliminary data are supportive and compelling to support the hypothesis and feasibility of the experimental plan.
- The studies are feasible in the time frame provided.
Principal Investigator (PI) and Research Team
- The PI is an accomplished investigator and is well funded, though productivity, in terms of publications, is modest.
- The collaborating investigators are appropriate and will provide the necessary expertise in animal models and reagents, though the publication record of the collaborators is also modest.
Responsiveness to the RFA
- There was some debate as to whether the project is responsive to the RFA. Animal models are eligible under the Exploratory Concept Award track but the goal of the RFA is to impact human stem cell biology. Some reviewers felt this proposal would be translatable to the human, and, therefore, impact human stem cell biology. Other reviewers felt that the exclusive use of an animal model was not necessarily responsive to the RFA. These reviewers thought the applicant did not sufficiently justify how the proposed animal model work would impact human stem cell biology and should have proposed some experiments demonstrating the finding could be translated to the human system.