Role of Renal and Endothelial Progenitors in Fetal Kidney Reconstitution

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Project 2 proposes to characterize, isolate, and propagate renal progenitor cells from developing human and from nonhuman primate kidneys. The purpose of these experiments is to enable reconstitution and repair of the diseased, damaged, but developing fetal kidney, by transplanting healthy progenitor cells with the capacity to differentiate into cell types and tissue that will repopulate and reconstitute the affected organ. This is a novel and clinically relevant proposal. Work to date in the field has focused on describing changes in the fetal kidney when obstructed, but these efforts have largely been restricted to the postnatal rodent kidney. Our fetal monkey model of unilateral ureteric obstruction is arguably the best model available to study this disease and strategies to treat it. The proposal is driven by the fact that the clinical condition of fetal urinary tract obstruction is one of the most important conditions affecting young children with kidney disease. The work proposed in this application brings together the support and expertise of a number of leaders in the field of stem and progenitor cell biology, fetal kidney disease, and fetal models of disease and intervention. At the successful completion of the studies proposed in this Project we are hopeful that we will be poised to embark upon potential intervention trials in the human fetus with lower urinary tract obstruction. Presently in many centers across North America, fetuses are selected for invasive in utero fetal urinary tract shunting based upon antenatal maternal ultrasound imaging. The collective results of these interventions have been somewhat disappointing due in part to the non-standardized patient selection, to the inaccuracies of in utero diagnosis, and to an as-yet-complete understanding of the pathogenesis of renal damage in urinary tract obstruction. While in utero relief of the obstructed kidney during the critical time of nephrogenesis is necessary to optimize outcome, it appears that it is likely not sufficient. Experiments proposed using human renal progenitor cells in obstructed nonhuman primate kidneys brings us as close as we can to the next step of intervention in humans. These next steps will be guided by the results of this proposal and by the subsequent development of well-designed randomized controlled trials in human fetuses. BC Children's Hospital, Vancouver, British Columbia PHS 398(Rev. 09/04) Page 134 Form Page 2 Principal Investigator/Program Director (Last, First, Middle): Tarantal, Alice F (Project 2) KEY PERSONNEL. See instructions. Use continuation pages as neededto provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name eRA Commons User Name Organization Role on Project Matsell, Douglas G. BC Children's Hospital Project Leader Yoder, Men/in C. Indiana University Co-Investigator OTHER SIGNIFICANT CONTRIBUTORS Name Organization Role on Project Human Embryonic Stem Cells E3 No Q Yes If the proposed project Involves human embryonic stem cells, list below the registration number of the specific cell llne(s) from the following list: http://stemcells.nih.gov/reqistrv/index.asp. Usecontinuation pages as needed. If a specific line cannot be referenced at this time, include a statement that one from the Registry will be used. Cell Line Disclosure Permission Statement. Applicable to SBIR/STTR Only. See instructions, d Yes d No PHS 398 (Rev. 09/04) Page 135 Form Page 2-continued Number the following pages consecutively throughout the application. Do not use suffixes such as 4a, 4b. Principal Investigator/Program Director (Last, First, Middle): Tarantal, Alice F. DETAILED BUDGET FOR INITIAL BUDGET PERIOD DIRECT COSTS ONLY PERSONNEL (Applicant organization only) % TYPE EFFORT INST. ROLE ON APPT. ON BASE NAME PROJECT (months) PROJ. SALARY Principal Douglas G. Matsell 12 10.0 176,000 Investigator Michael J. Butt Technician 12 100.0 28,688 SUBTOTALS ^ CONSULTANTCOSTS None EQUIPMENT (Itemize) None SUPPLIES (Itemize by category) Microarray analyses Histology, immunohistochemistry, and in situ hybridization analysis Cell characterization, isolation, and culture TRAVEL None PATIENT CARE COSTS INPATIENT OUTPATIENT ALTERATIONS AND RENOVATIONS (Itemize by category) OTHER EXPENSES (Itemize by category) CONSORTIUM/CONTRACTUAL COSTS (Project 2) FROM THROUGH 09/01/05 08/30/06 DOLLAR AMOUNT REQUESTED (omitcents) SALARY FRINGE REQUESTED BENEFITS TOTAL 15,042 2,558 17,600 22,950 5,738 28,688 37,992 8,296 46,288 1 0 0 7650 6016 6033 19,699 0 DIRECTCOSTS SUBTOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD (Item 7a,Face Page) $ 65,9871 CONSORTIUM/CONTRACTUAL COSTS FACILITIES ANDADMINISTRATIVE COSTS 5,279 TOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD $ 71 ,2661 SBIR/STTR Only: FEE REQUESTED PHS 398 (Rev.09/04) Page 136 Form Page 4