Research Leadership 10
Kidney function is essential for removing the wastes that result from normal cell function and maintaining water and salt balance in our internal tissues. These actions are carried out by roughly a million nephrons within the kidney that filter all the body’s blood roughly once every 1-2hours. The kidney also regulates other tissues controlling blood pressure and blood cell composition, and regulating the strength of bone by activating vitamin D. Chronic kidney injury over time results in a loss of normal kidney function leading to end stage renal disease (ESRD). ESRD affects 500,000 Americans and its prevalence is increasing with a rise in diabetes and hypertension. ESRD is associated with significant morbidity and mortality: ultimately kidney transplant is the only cure but for every four patients requiring a transplant there are only enough available kidneys to help one. Life-threatening kidney injury also occurs through acute damage particularly in hospital settings were infection, toxic drugs or ischemia during surgery kills cells in the nephron shutting down the kidneys. Animal studies indicate that the kidney is unable to make new nephrons: the full complement of nephrons for live are established prior to birth. However, the damaged nephron has a limited capacity to restore activity through the regeneration of missing cells by their surviving neighbors. Kidney stem cells give rise to all specialist parts of the complex nephron structure during kidney development. New genetic approaches in the mouse have enabled the isolation of these stems cell providing an opportunity to develop strategies to propagate and differentiate kidney stem cells into nephrons in the tissue culture dish. We expect that the insights gained from these studies will facilitate the translation of de novo nephrogenesis to human nephron cultures, and as a result, the development of new approaches to study and treat kidney disease. An alternative approach comes from the observation of limited self-repair by cells within damaged nephrons. The molecular and cellular processes at play in the damage-repair responses are largely unknown but elucidating these mechanisms will facilitate development of novel strategies to either augment the repair process following damage or prevent tubule damage in the first instance within at risk patients. Mouse models again provide a way forward to this long-term goal. By isolating repairing cells, and comparing gene expression signatures amongst damaged, repairing and healthy cells, we will identify repair specific responses and test the ability of candidate repair regulators to enhance the restoration of kidney function.
Statement of Benefit to California:
Approximately 1% of Medicare enrollees in the State of California have End State Renal Disease and this number will rise. There is no effective cure aside from kidney transplantation, too few donors, and a high morbidity and mortality associated with long-term dialysis. Approximately 5-7% of hospitalized patients experience acute kidney injury, a leading cause of mortality in institutionalized settings. The target of kidney injury and disease is the nephron, all nephrons form during fetal life and self-repair within nephrons is thought to restore normal function. Through identifying conditions that support stem cells capable of new nephrogenesis and generating new nephrons from these cells, we will be able to explore approaches to restoring kidney function that are not currently possible. Further, the identification of factors associated with normal nephron repair will enable functional investigation of their potential clinical significance in kidney injury models. Given the fiscal cost of kidney disease within the State, the toll of kidney disease on patients and their families, and the lack of alternatives – developing approaches that treat disease would have a significant impact.
The candidate principle investigator (PI) is a mid-career scientist who leads a robust research program focused on kidney development. The candidate has already made major contributions to an understanding of signaling pathways in mammalian development with particular recent emphasis on the genetic pathways that underlie normal and pathological processes in kidney differentiation. The proposed research program will focus on understanding the properties and potential of kidney stem/progenitor cells and on devising strategies to generate new nephrons, the functional units of the kidney. Among the goals of the planned research is the refinement of nephron progenitor/stem cell cultures, the development of procedures to generate human nephron-like structures in vitro, and an investigation of cell-specific repair responses to acute kidney injury. These efforts should substantially advance the field toward novel therapies for kidney disease. Reviewers characterized the proposed research as addressing an extremely important but understudied area of regenerative medicine. Given the complexity of the kidney and its function, reviewers felt that the PI’s approaches based on mechanistic studies of kidney development and exploiting multiple investigative strategies, could lead to new, important and transformative discoveries. The PI was described by reviewers as an exceptional scientist and one of the leading young developmental biologists. The candidate has already made seminal contributions to an understanding of fundamental mechanisms in mammalian embryonic development and has been a leader in developing animal models for the study of organ systems. He/she has been extremely productive, publishing a number of important and influential papers in the top journals such as Cell, Nature, Developmental Cell and Science. The candidate has received substantial extramural funding and has ongoing research support from the NIH and industry sources. The PI’s work is widely respected; he/she has received several prestigious awards and has been invited to present seminars at leading institutions and scientific meetings. The PI has demonstrated leadership through chairing of NIH review panels, organizing workshops and meetings, serving on the editorial board of major journals, chairing an academic department at a major university, and serving on the executive committee of a leading stem cell institute. Leaders in stem cell and developmental biology praised the candidate in superlative letters. They cited his/her groundbreaking discoveries concerning developmental signaling pathways and described him/her as a ‘world-class” scientist, pioneer and leader in the field who is engaged in careful, thorough and cutting-edge research. Reviewers viewed the institutional commitment as outstanding. This commitment includes a substantial recruitment package featuring abundant lab space and resources for the PI’s research program as well as devoting funds for an entirely new department under the PI’s leadership. Reviewers further regarded the candidate’s recruitment as augmenting a strong stem cell community and likely to attract other top researchers to the institution, catalyze productive collaborations, and lead to novel therapeutic development. The recruitment was recognized as extremely promising and beneficial for both the candidate and the applicant institution. In summary, this is an extremely strong application from a leader in developmental biology. Major strengths include the candidate’s exceptional productivity and contributions to the fields of mammalian embryology and kidney development, the significance and potential of the research program, the PI’s proven leadership capabilities, and the outstanding institutional commitment.