Mahesh H. Mankani M.D., Associate Professor of Surgery in Residence
 
 Since my appointment as a post-doctoral fellow in the Craniofacial and Skeletal Diseases Branch at the National Institute of Dental and Craniofacial Research (NIH), and then during my tenure here on the UCSF faculty, my long-term career goal has been to establish an interdisciplinary program to treat patients’ bone abnormalities with cell-based therapies. My short-term career goal has been to establish an active research program exploring the role of bone marrow stromal cells (BMSCs) in bone formation and remodeling, focusing on ways to enhance normal bone formation in patients with osteoporosis. I plan to seek extramural grant support in the form of an NIH R01 in October 2007 for this program.

In seeking to achieve these goals, I have focused my research in two areas: 1) developing techniques to engraft BMSCs and engineer bone, and 2) describing the role of BMSCs in bone formation and repair.

My first research area centers on the development of techniques to engraft BMSCs and engineer bone. My colleagues and I have found that:
1) The size of hydroxyapatite particles influences BMSC-bone formation by its ability to bring cells in proximity while regulating vascular ingrowth. This has allowed us to optimize bone formation via matrix selection. (Ref #15)
2) BMSCs transplants can be organized around arterio-venous leashes, allowing the creation of pre-fabricated and tailored bone constructs for reconstructive purposes. (Ref #16)
3) qCT scanning can be used to characterize the extent of bone formation in alloplastic transplants. This is significant because it will permit us to non-invasively evaluate BMSCs in patients, eliminating the need for an open biopsy. (Ref #20)
4) BMSC transplants can be used to augment a rodent mandible and repair its cranial defects, and have long-term stability (22 months). This validates BMSC transplant performance over a vastly longer time span than previously described. (Ref #23)
5) BMSC transplants can close large-animal bone defects and provide long-term stability (18 months), paralleling our proposed clinical study. This validates the techniques proposed for our clinical study. (Ref #22)
These and associated efforts have yielded 8 manuscripts in peer-reviewed journals, including 6 on which I was the first author, 19 abstracts in meetings proceedings, one patent, and two NIH invention reports.

A significant ongoing project is the preparation of a Phase I clinical trial for placement of autologous BMSCs to close calvarial bone defects in patients. This is a joint effort with my former NIH chief, Pamela Gehron Robey PhD, in which we serve as co-PIs. My contribution has been the preparation of an IND application for submission to the FDA, outlining the safety and efficacy of our techniques for BMSC preparation and transplantation, and drawing heavily on my extensive pre-clinical experience with this unique technology. I will be responsible for conducting the overall study and for managing all patient-related issues, including recruitment, operative procedures, post-operative testing, and data analysis. Dr. Gehron Robey will coordinate all product-related issues, including BMSC preparation and cell testing. The study, which would likely begin in December 2007, would derive primary funding from both NIH intra-mural and extra-mural sources.

My second research area focuses on describing the role of BMSCs in bone formation and repair. This research first focused on describing the pathophysiology of McCune-Albright syndrome via BMSC dysfunction. I am now using our progress with McCune-Albright syndrome to examine the role of BMSCs in osteoporosis. The goal of this work is to develop techniques to improve the mechanical properties of bone using transplants of autologous culture-expanded BMSCs, with the clinical goal of decreasing the risk of osteoporosis-associated fractures. We have 1) developed and validated a model for the formation of osteoporotic bone using transplanted BMSCs, 2) characterized differences in BMSCs from normal and estrogen-depleted donors, and 3) confirmed that transplanted BMSCs are responsive to endogenous estrogen levels when forming new bone. Based on preliminary data collected over the past 18 months, I am preparing an application for funding via the R01 mechanism for the October 2007 cycle. My UCSF collaborators include Grayson Marshall (in the School of Dentistry) and Robert Nissenson (in the Department of Medicine). To date, work in this area has yielded 4 manuscripts in peer-reviewed journals, 15 abstracts in meetings proceedings, and 1 book chapter.

Through this research program, I hope to describe the role of BMSCs in osteoporosis-associated bone weakness and to demonstrate the efficacy and safety of BMSC transplantation as a potential therapy. Successful completion of these efforts would form the basis of my ultimate career goal of establishing an interdisciplinary program at UCSF to treat patients’ bone abnormalities with cell-based therapies.