New Faculty Physician Scientist
$2 313 681
As our population continues to age, a concomitant increase in the incidence of diseases involving the musculoskeletal system is expected. Current approaches to address skeletal injuries and defects are limited, and thus a pressing need exists for the development of alternative cell-based strategies for bone reconstruction. Stem cells represent a powerful tool with the potential to treat a wide range of diseases. Ultimate clinical application, however, has been hampered by the limited ability to effectively guide these cells in a safe manner toward desired targets. However, we believe that the way genetic material is regulated may be exploited to coax stem cells toward bone formation. We will test this theory by first determining all the changes that occur in these cells in response to compounds known to enhance the generation of bone. We will then look to mimic these changes and evaluate the strength of this approach to guide our stem cells toward bone. Finally, we will employ a mouse model to investigate the both the safety and efficacy of our approach to promote human stem cell-mediated bone regeneration in an animal engineered to not reject human cells. Together, these studies will lead to the development of a powerful therapeutic strategy to improve skeletal regeneration in our aging population.
Statement of Benefit to California:
The most significant social, political, and economic problem we face in California and in the United States is our aging population. Nearly 20% of the population in this state is presently 55 years or older. Worldwide, within the next five years, the WHO reports that the number of people over age 65 will outnumber those under 5. As our age demographics continue to shift, a concomitant increase in incidence of diseases involving the musculoskeletal system is expected. This stems from a multitude of etiologies including post-surgical, post-traumatic, and degenerative conditions. In 2007 alone, the biomedical burden attributed to diseases of the musculoskeletal system was reported to exceed 26 billion dollars, and this figure has continued to increase in more recent years at an estimated rate of 8.5% annually. Treatment of bone related problems, however, is not limited to the elderly, as children born with congenital anomalies also frequently require skeletal reconstruction. In light of these facts, better approaches to the treatment of skeletal defects and deficiencies must be developed. Our proposal addresses this need by developing a strategy to harness the regenerative potential of stem cells in a safe and effective manner. As studies have shown the ability for stem cells to form bone, we explore this potential with the ultimate goal of actualizing a powerful therapeutic strategy to treat skeletal deficiencies for citizens of California and beyond.
Executive Summary The applicant proposes to pursue the molecular mechanisms by which bone morphogenetic proteins (BMPs) mediate bone formation, or osteogenesis, from human pluripotent stem cells (hPSC). The study will focus on the role of a specific class of epigenetic regulators and develop approaches to manipulate stem cells to achieve improved efficacy and safety of hPSC-based therapies for bone regeneration. To accomplish this, the applicant proposes first to characterize epigenetic changes in hPSCs in response to BMP (Aim 1). Next, the applicant will test the functional significance of identified epigenetic regulators by assessing their ability to mimic BMP treatment (Aim 2) and to promote osteogenic differentiation in vitro (Aim 3). Finally, using an in vivo model of bone defects, the applicant will determine whether manipulation of the identified regulators improves the bone forming potential of hPSC while reducing the occurrence of teratomas (Aim 4). Research Plan - The repair of bone defects including those due to abnormal development, tumors or trauma is an important clinical goal. As efficient methods to address such problems do not currently exist, the proposed directed differentiation of stem cells is a potentially viable solution. - The rationale for the proposed approach is not compelling. Although manipulation of epigenetic regulators can have clinical potential, the applicant did not provide a rationale as to why manipulation of epigenetic regulators that act downstream of BMP would enhance osteogenesis over BMP treatment alone. - No evidence was provided that the type of epigenetic regulator targeted in the proposed study plays a specific role in this system. - Preliminary data were provided to support for most of the necessary experiments. However, data to support the feasibility of manipulating the expression of the targeted class of epigenetic regulator were not included. - Reviewers were unclear as to how many epigenetic regulators identified in Aim 1 could be tested in Aim 2; the applicant did not discuss the possibility that the simultaneous manipulation of multiple epigenetic regulators may be required to observe the anticipated effects. - Reviewers cautioned that the silencing of the targeted epigenetic regulators might not persist throughout the duration of the proposed in vivo experiments in Aim 4. Furthermore, the maximum proposed duration of those experiments was not viewed as sufficient to establish the safety of the cells. Principal Investigator - The Principal Investigator (PI) is a practicing craniofacial surgeon and clinician-scientist with 50% protected time for research. The plan to integrate his/her research and clinical expertise appeared well developed. - The PI’s publications appeared in solid and relevant basic science and surgical journals, though none are high profile papers. - The selection of two very accomplished mentors is highly appropriate for the proposed project and could substantively contribute to the applicant’s career trajectory. Letters from these individuals clearly indicated their commitment to the applicant. - Reviewers expressed differing views on the applicant’s career development and mentoring plans. Some felt they were well designed whereas others found them to be vague and lacking in clear milestones and specific timeframes. Institutional Commitment - Although reviewers felt there is strong support for the applicant from the institution, they expressed concerns about the laboratory space provided to the applicant and questions about the applicant’s degree of independence. - The applicant has access to exceptional core facilities and will be surrounded by highly regarded faculty in stem cell biology. - The applicant institution has an outstanding track record of supporting junior investigators and physician-scientists, and has a strong investment in stem cell research. Responsiveness - This proposal is highly responsive to the RFA. The applicant proposes to test hPSC as cell sources for promoting bone regeneration.