Stem cells are endowed with the ability to self-renew, that means to give rise to other cells with the same potential to regenerate a tissue. Recently, we found a gene that also regulates this mechanism. In addition, expression of high levels of this gene can reduce the number of stem cells in the bone marrow and possibly the brain. This gene is expressed in the Chromosome 21 and hence can potentially contribute to the pathology of people with Down Syndrome (people with Down Syndrome has three copies of Chromosome 21). In line with that, we observed that mouse models for Down Syndrome have less stem cells in their bone marrow.
We therefore want to study the mechanism of action of this gene and its effects on stem cells in the bone marrow and other tissues.
Outcomes from this study will shed more light in understanding not only the normal process of stem cell maintenance, but also in deciphering the complex biology underlying Down Syndrome. In particular, this study will potentially help to understand why Down Syndrome carriers have a defect in learning. We hypothesize that a defect in neural stem cells leads to abnormal brain development. If so, then pharmacologic agents that inhibit the function of this gene might ameliorate the pathology of Down Syndrome.
Another important aspect of our research on this pertains to cancer development: indeed cancer initiating cells take advantage of the normal self-renewal machinery to proliferate without restraint. Our preliminary data suggest that high levels of this gene could potentially counteract some solid tissue tumors, putting a brake on cancer cells proliferation. Interestingly, people with Down Syndrome have a much lower risk of developing solid tumors than the general population. We will use human cancer samples, in particular breast and colon tumors, that we receive directly from Stanford Hospital to analyze this gene’s contribution to cancer development. These studies will give us important hints to discover alternative strategies for cancer treatment.
The goal of the proposed research is to shed more light in understanding not only the normal process of stem cell maintenance, but also in deciphering the complex biology underlying the Down Syndrome. This study will potentially help to understand i) whether a defect in stem cell self renewal contributes to the Down Syndrome phenotype, ii). why Down Syncrome patients have a lower risk of solid tumors. These studies potentially could identify an enzyme which could be drugged to partially ameliorate Down Syndrome pathology. This clearly would provide great benefits to the people of California by minimizing suffering of patients and families while also decreasing the costs associated with care of these patients.
The goal of this application is to characterize the role of the USP16 protein in regulation of hematopoietic stem cells (HSC) and hematopoiesis, and to explore its potential role in the pathology of Down’s Syndrome (DS). UPS16 is a histone deubiquitinating enzyme that appears to oppose the action of a key transcriptional repressor that is important for self-renewal in HSC and several other adult stem cell populations. UPS16 expression appears to correlate with the number of HSCs in the bone marrow and importantly, patients with Down’s Syndrome (DS) have an extra copy of UPS16. As DS patients have reduced rates of solid tumors, the applicant seeks to determine whether USP16 expression may lead to protective effects against cancer. Two specific Aims have been proposed to explore these phenomena. In the first, the applicant will examine the potential of UPS16 to counteract the activity of a key repressor in the bone marrow and analyze UPS16 function in regulating HSC self-renewal in DS. The second aim is to evaluate whether UPS16 can function as a protective factor from cancer by limiting cellular self-renewal.
Significance and Innovation:
- The proposed research is highly significant in that it could lead to improved treatments for DS as well as cancer.
- This study could provide new insights into mechanisms regulating stem cell renewal and advance an understanding of the relationship between stem cells and cancer risk.
- Reviewers described the focus on USP16/key transcriptional repressor balance and its potential importance for determining HSC and progenitor cell numbers as innovative and novel.
Feasibility and Experimental Design:
- The feasibility of this study is supported by substantial preliminary data obtained with mouse models.
- Reviewers found the proposed experiments to be generally well thought out, logical, and feasible.
- The proposal was weakened by uncertainty about whether the mouse data will translate to the human situation.
- Reviewers expressed some concern that the applicant did not address the increased incidence of myeloproliferative disorders and leukemia in DS patients, thereby weakening the proposal’s rationale for examining the role of USP16 in oncogenesis.
Principal Investigator (PI) and Research Team:
- The PI is highly experienced and eminently qualified to conduct the proposed research.
- The research team has all necessary expertise and is well suited to carry out the proposed investigation.
Responsiveness to the RFA:
- The proposed research is responsive to the RFA in that it focuses on molecular mechanisms regulating HSC behavior, studies human cells, and has implications for human cancer stem cell biology.