Basic Biology V
$1 161 000
Hematopoietic stem cell function and regeneration are often impaired with age, creating a chronic immunosuppressed state, increasing susceptibility to disease and preventing the effective delivery of many critical treatments like chemotherapy or radiation. The experiments proposed are designed to define the mechanisms that maintain normal stem cell function and that are compromised during aging and to develop effective approaches to circumvent this critical problem. These studies are important because a better understanding of how stem cell function changes with age and the ability to activate cellular and molecular elements may improve hematopoietic function during aging.
Statement of Benefit to California:
Developing new approaches to effectively reverse the decline in health that is associated with aging can be a challenging task. The experiments proposed here have broad implications in this regard, and will not only define a critical pathway associated with the age-related decline in stem cell self-renewal and function, but will seek to reverse this decline by identifying pathways that can be targeted to enhance the regenerative potential and functional capacity of stem cells. These studies are critical because they have the potential to fundamentally transform treatment strategies for a wide variety of diseases and conditions that afflict the elderly, including chronic immunosuppression, cancer and degenerative disorders, which would be a direct benefit to all citizens in the State of California.
This Fundamental Mechanisms application focuses on a molecular hypothesis to explain the observation that the regenerative capacity of hematopoietic stem cells (HSC) is diminished with age. Preliminary data in the murine system have led to the hypothesis that a particular protein is an important regulator of this regenerative capacity, perhaps through an effect on DNA damage repair. This proposal seeks to examine the role of this protein in human HSC function and aging. The specific aims are (1) to determine if loss of the human protein induces an aged phenotype in human HSCs in vitro and in vivo, (2) to determine if increased expression of the protein enhances HSC function and decreases the aged phenotype, and (3) to define the downstream molecular targets of the protein of interest. Significance and Innovation - The protein of interest has already been shown to regulate self-renewal of a number of different stem cell populations. However, the identification of a role for this protein in aging of human HSCs would be a novel observation and may identify a new target for improving the regenerative potential of HSC from aged individuals. Feasibility and Experimental Design - The preliminary data presented are entirely from the murine system, and there are no data linking this protein to aging in human HSC. If those data cannot be obtained, the rationale for the subsequent experiments is flawed. - The mechanism(s) by which this protein may regulate the regenerative capacity of hematopoietic stem cells (HSCs) are not clearly defined. The preliminary data don’t strongly support the assertion that there is a role for the protein of interest in DNA repair. - Specific Aims 2 and 3 are highly dependent on the success of Aim 1, which may be problematic if Aim 1 cannot be achieved. Aim 3 appears to be biased toward the DNA repair hypothesis and a less biased approached would be preferable. - Overexpression of the protein of interest may be tumorigenic in addition to its regenerative effects, but this possibility was not addressed. Principal Investigator (PI) and Research Team - The co-Investigators have appropriate expertise and strengthen the team, but there was concern about whether their level of commitment was adequate. - The PI has been productive with a strong track record of publications Responsiveness to the RFA - The application is responsive to the RFA in that it proposes to study the molecular changes behind aging of HSC, and to identify targets for improving function of aged HSC.