New Faculty Physician Scientist
$3 084 000
Skeletal muscle makes up 40% of our bodies, dictates our form, is responsible for our ability to move, express ourselves, eat, breath and to look around. Restoration or preservation of the body’s normal form and function is the central goal of regenerative medicine and the central focus of my clinical specialty of plastic and reconstructive surgery. Skeletal muscle injury and disease are major sources of morbidity that affect millions. The potential for treating these ailments with regenerative approaches that use stem cells is enormous because skeletal muscle naturally has its own stem cell population. However, to make human muscle stem cells a usable clinical tool we need to be able to characterize them, transplant them, and induce them to function effectively. To accomplish these goals, our objectives are to identify appropriate human muscles to harvest stem cells from, to develop techniques to transplant them, and to test them in models of diseases. This work is expected to lead directly to treatments for patients with several disabling muscle degenerative conditions that affect small but critical muscles that could be regenerated with localized muscle stem cell transplants. Examples include facial paralysis or loss of hand function, and conditions affecting the eye muscles causing vision loss. This work also lays the groundwork for tissue engineering of muscles, and will contribute to approaches to correct genetic muscle defects or treat other systemic muscle diseases.
Statement of Benefit to California:
Skeletal muscle injury and disease are major sources of morbidity that affect Californians of all ages, including the veteran population. Regenerative medicine and stem cell biology offer great potential for opportunities to improve upon current treatments and to develop approaches for many of the muscle ailments that remain essentially untreatable. Skeletal muscle stem cells have been well characterized in mice, and preliminary evidence suggests similar approaches in humans will enable clinical translation. Therefore, the proposed research seeks to develop stem cell therapies that will directly impact muscle ailments that are at the root of diverse deformities and disabilities of the face, body and limbs. California is the birthplace of many of the great advances in reconstructive surgery, including microsurgery and muscle flaps, largely through the support of its people, and their pioneering spirit. In turn, Californians have benefited and continue to benefit from the newest and best approaches that reconstructive surgery has to offer. We propose to continue to improve reconstructive and regenerative options for the citizens of California by building on our strong historical foundation to address current needs. Our research will carry on this tradition because of our focus on problems of form and function affecting many of our citizens, the logical path to muscle stem cell clinical application, and the unique clinical and scientific focus and potential of our team.
Executive Summary The goal of this proposal is to develop ways to restore small but important muscles in distinct anatomic locations by utilizing autologous human skeletal muscle stem cells (hMuSC). Three aims have been proposed to accomplish these goals. In the first aim, the applicant will identify the most appropriate skeletal muscles from which to obtain optimal hMuSCs. In the second aim, the PI will determine the optimal transplantation approach and cell dose. The third aim will evaluate the therapeutic potential of this approach with studies involving transplantation of hMuSC into preclinical models of localized muscle dysfunction. Research Plan - Reviewers were enthusiastic about the focus of the proposed work on small muscles and found the use of hMuSC for muscle repair to be innovative. - The proposed research could have a major impact on the treatment of degenerative muscle conditions such as those causing facial paralysis, impaired hand movement and incontinence. - The scientific rationale is logical, and the planned experiments are well thought out. - The project is technically challenging, but reviewers found the preliminary data showing that cell isolation and transplantation are feasible to be compelling. - Alternatives were provided for various experiments, and potential risks were addressed. Principal Investigator (PI) - The PI is a physician-scientist with an excellent track record as an independent investigator. The major research focus area for the PI has been regenerative medicine and stem cell biology with emphasis on muscle regeneration. - The PI has a very strong publication record with several papers in top-tier journals. - Reviewers praised the PI’s selection of two excellent and very experienced mentors who are well established, internationally known stem cell and clinical scientists, respectively, with a history of mentoring successful clinician scientists. - The PI presented a comprehensive career development plan with clear milestones for professional development and for translation of this research into clinical therapies. - Reviewers had some minor concerns about lack of skills in certain areas but were confident these skills would be covered through collaborations and could be obtained easily with proper training. Institutional Commitment - It was evident from the supporting letters that the applicant institution is strongly committed to ongoing support for the PI’s career development. - The applicant institution provides an outstanding environment offering full access to university core facilities; the applicant has been provided with ample laboratory space and with protected time for research. Responsiveness - Reviewers found the application to be highly responsive to the RFA as it is focused on translating basic stem cell knowledge in a realistic way towards clinical application.