Funding opportunities

Mechanism of Tissue Engineered Small Intestine Formation

Funding Type: 
New Faculty II
Grant Number: 
RN2-00946
Principle Investigator: 
Funds requested: 
$3 240 000
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Statement of Benefit to California: 
Review Summary: 
The application is focused on short bowel syndrome, a childhood disease associated with significant morbidity and mortality. Currently small bowel transplants are the standard of care, but donors are in short supply, and the surgery and post-operative course are associated with poor long-term survival. The applicant proposes study of a novel alternative to transplantation of donor grafts, the use of a tissue engineered small intestine (TESI), created ultimately by autologous cells cultured to generate small intestine organoid units on biodegradable polymer scaffolds. The applicant plans to optimize and characterize growth of TESI using mouse cells, and to trace the lineage origins of the operant stem cell population in transgenic mouse models. TESI will also be tested functionally for responses to growth factors, and electrophysiologically. Then using human cells (obtained from surgical explants) the applicant will generate TESI and implant them into immunocompromised mice to determine function after engraftment. In the long-term the applicant plans primate studies based on the mouse work, but is not requesting funding for the large animal model work. An important strength of the application was the straightforward design of the proposed studies. The stem cell populations will be characterized in sufficient detail to standardize the translational protocols. Reviewers were impressed by the quality of the preliminary data, in particular the normal microscopic appearance and architecture of the TESI generated so far, and the development of a surgical approach to the mouse. Reviewers were concerned that the developmental biology approaches were not detailed sufficiently, and because the markers chosen were not necessarily specific for the progenitor cells of interest and bioluminescence approaches not robust, this part of the research plan may run into trouble. In response to these concerns, the reviewers suggested more focus on the translational issues in surgical models. The reviewers all felt that the applicant had the ideal clinical-scientist background to bring into stem cell biology and regenerative medicine. A weakness of the proposal was the lack of detail on how the applicant planned to scale up the experiments from mouse to primate, and the reviewers thought this part of the proposal poorly developed. In particular a discussion of how the information obtained in mouse studies will be applied in primates would have been welcomed. The reviewers were left wondering about how the applicant envisioned the surgical technique and immunosuppressive approaches for the primate studies. In the end, the potential for the rodent work to yield important information over-rode concerns about the primate studies, which are premature, and if set aside until the appropriate time, still leave a research plan that can stand on its own to yield significant insights into intestinal biology and therapy. The applicant is a pediatric surgeon who trained at top medical school and residency programs, and has been an Assistant Professor of Surgery for 2 years. Letters of support from a previous mentor cited the applicant’s gift for independent thought and high intellectual capacity, and the applicant has won numerous awards. The applicant does not yet have independent publications. The applicant proposes to supplement clinical expertise with formal coursework and training in developmental biology, and has outlined an elaborate and ambitious career development plan. The strong institutional support is reflected in the several letters of reference, and speaks to the enthusiastic commitment to the applicant by the institution. Further, the institution and clinical department are protecting 75% of the applicant’s time for research in a unit where the applicant is surrounded by other investigators interested in gut regeneration. One mentor is a noted expert in the field and, with the other diverse mentors, will bring tremendous power to the application. Overall the potential impact of this project could be tremendous, and could result in a source of intestinal replacement therapy that does not require immunosuppression. The work has implications for other intestinal diseases as well.
Conflicts: 

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