Basic Biology V
$1 121 525
Most kidney diseases leading to End Stage Renal Disease (ESRD) originate when podocytes, the key cells in maintenance of the glomerular structure and function, are lost. Kidney failure can become irreversible because podocytes cannot be replaced, since they have very limited regenerative capability. Very little is known about the origin of renal cell progenitors, about the development of podocytes during the embryonic phase and it is also unclear which are the major important signaling pathways that regulate human kidney development. There are no in vitro systems that can be used in order to study the biology of kidney progenitor cells as well as the specification of podocytes. Therefore, a new culture system that will allow kidney progenitors to be propagated, not only maintaining their self-renewal, but that can also be induced to become fully mature kidney cells, is needed. We have identified a novel kidney progenitor population within the amniotic fluid (hAKPC-P) that expresses markers of embryonic kidney cells and that under specific conditions can be differentiated into podocytes. In this project we propose to study how self-renewal and kidney specification is regulated in hAKPC-P. In conclusion, we believe that hAKPC-P will help to elucidate the biology of human kidney cells, in addition to understanding the causes of diseases resulting from loss and/or damage of kidney cells, like the podocytes.
Statement of Benefit to California:
The State of California is home to some of the nation's best kidney treatment centers. Having our laboratory next to one of California's busiest pediatric renal transplant programs we have been aware of the need for new and better alternative therapies to benefit our patients. In particular we focused our attention on chronic kidney disease, which is increasing every year. The kidneys, differently from other organs, possess limited regenerative capability, thus finding new stem cells/kidney progenitors that can substitute for damaged renal cells could make a significant impact in this field. These discoveries provide our child patients, as well as the adult patients in California, with alternative technologies that would benefit their longevity and quality of life. We have identified a new population of renal progenitors within the amniotic fluid, which can be easily obtained, stored, propagated and differentiated into renal cells, without genetic manipulation, thus eliminating some concerns over clinical compatibility and ethical concerns. In this study we intend to characterize these specific renal progenitor cells as a potential tool for understanding the molecular mechanisms that lead to renal differentiation. This knowledge will likely improve our understanding of common diseases resulting from loss and/or damage of renal cells. CIRM funding will ensure a competitive advantage for California in this innovative direction.
This Fundamental Mechanisms Award proposal is focused on examining the molecular mechanisms involved in human kidney cell specification and development. The applicant has identified a kidney progenitor cell population in human amniotic fluid and proposes to study the role of various signaling pathways in balancing self-renewal versus differentiation in this cell population. The applicant will also investigate if the identified kidney progenitor cells represent a multipotent or unipotent cell population. Significance and Innovation - The project is unlikely to reveal any new mechanistic insights into kidney development. It is designed to confirm in human cells what is known from rigorous animal studies, and if the data fail to confirm previous studies, it is unclear how this work would lead to new definitive conclusions about human kidney development. - There is a lack of human cell models of kidney development and almost no access to mature kidney cell types of clinical interest. If the cells identified can model kidney development and provide a renewable source of kidney cell types, this would have a major impact. Feasibility and Experimental Design - The proposal lacks scientific rigor. For instance, reviewers were not convinced by the preliminary data that the isolated amniotic fluid cells represent bona fide kidney progenitors or that the proposed assays will demonstrate that the differentiated cells are authentic kidney cells. - The proposal is not designed to systematically test hypotheses. - The proposal is poorly written and the goals of the specific aims are not well reflected in the experimental design. Principal Investigator (PI) and Research Team - The PI is a junior investigator who has been well trained and appears to have the necessary background to complete many of the studies. - There are several excellent collaborators that will assist the PI. Responsiveness to the RFA - Reviewers were not convinced that the human cells isolated from the amniotic fluid are genuine stem cells. Thus, the application may not be responsive to the RFA.
- Ali Brivanlou