Funding opportunities

Treating endometriosis by restoring signaling defects in the endometrial stem cell niche

Funding Type: 
New Faculty Physician Scientist
Grant Number: 
Funds requested: 
$3 064 711
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
This research will investigate whether the stem cells in a woman’s uterine lining cause endometriosis. Endometriosis is a chronic disease where tissue that normally lines the uterus grows in other parts of a woman’s body causing pain and discomfort. It typically begins around age 25 and lasts until menopause. Up to 10% of women are affected by endometriosis. It is a leading cause of infertility. There is no cure and treatments are often ineffective. The researchers believe that endometriosis may be caused by a miscommunication between one type of stem cell, the ‘uterine epithelial stem cell’, and its environment. This miscommunication may cause the cell to stop responding normally to progesterone, a hormone involved in a woman’s menstrual cycle. The researchers aim to test this idea by comparing the stem cells of women who have endometriosis with the stem cells of women who do not. They will look for differences in cell activity levels and in receptivity to progesterone. If reduced progesterone receptivity is found, they will repair the cells’ progesterone receptors and see if this prevents endometriosis. The final stage of the research will test medicine that can treat the disease. If it caused by reduced receptivity to progesterone, they will test existing FDA-approved drugs, known as histone deacetylase inhibitors to restore normal progesterone response. If it is caused by higher stem cell activity, they will test drugs to block this activity.
Statement of Benefit to California: 
Endometriosis affects 1.8 million Californian women for an average of 25 years each. When the number of affected individuals is multiplied by the duration of disease it yields the following alarming statistic: women in California suffer from endometriosis for a total of 43 million years (data extracted from the Center for Disease Control and the US Census 2010). By this measure, only arthritis and type 1 diabetes are worse chronic non-lethal diseases. Endometriosis affects women in their most productive years. It causes great pain, infertility and significantly increases their risk of developing migraines, anxiety and depression. The total cost of endometriosis to California is $25 billion a year: $20.1 billion is lost in productivity and $4.7 billion in medical care costs. Eleven hours of productivity is lost per women per week (Nnoaham et al., 2011) resulting in 972 million lost work hours a year in California. Treatment costs $2800 per woman per year (Simoens et al., 2007). This does not include treatments for secondary effects of endometriosis such as migraine. Developing a treatment based on this proposal will have the following benefits to California: 1) relief from the third worst chronic disease in California, 2) savings of billions of dollars from reduced care costs, 3) major revenues from regained productivity and 4) revenue from potential new technology and patents owned by the State and licensed to Californian companies.
Review Summary: 
Executive Summary Endometriosis is a chronic disease where endometrial tissue, the hormonally responsive epithelium and stroma that lines the uterine cavity, is found outside the uterus as ectopic tissue implants. The disease results in pain and infertility and affects up to 10% of women, yet little is known regarding the pathophysiology of the disease, and there are no effective treatments. The applicant hypothesizes that miscommunication between the endometrial stem cell niche and the endometrial epithelial stem cell occurs due to abnormal progesterone signaling, and this miscommunication promotes ectopic tissue formation. In this proposal the applicant plans to compare human endometrial tissue taken from normal and diseased individuals and define biological, progesterone signaling, and cellular differences in the endometrial stem cell niche in individuals with endometriosis. The applicant will also develop an in vivo mouse model of human endometriosis and use the model to demonstrate whether progesterone signaling in the niche plays a role in endometriosis and test the potential of several pharmacologic agents as therapeutic candidates. Research Plan - There is little data presented to support the hypothesis that inappropriate progesterone signaling is occurring in endometriosis. As Aims 2 and 3 are entirely dependent the success of Aim 1, which tests this hypothesis, and the results of Aim 1 are not obvious, this is a huge risk to the project. - The proposed hypothesis is novel and the proposal innovative. Further, if successful, the proposed research could have a major impact, as endometriosis is a substantial health burden - The applicant provides good preliminary data (PD) to support the existence of the described uterine epithelial stem cell population, however, this has not yet been definitively demonstrated. - Aim 3 is not well developed and lacks critical PD demonstrating the feasibility of the approaches. While the use of FDA approved drugs in this aim adds to the potential impact if successful, the applicant does not adequately describe the rationale for why the compounds were selected or how they might interact with the stem cell or niche. For this reason, the link between this translation-focused aim and the previous two basic research-focused aims is weak. - Overall, the proposal is logical and well written, although the applicant does make some inaccurate claims regarding the existing literature on endometriosis and should review the current literature in greater detail. - Aim 1 is straightforward and feasible and could provide insight as to whether the endometrial stem cell niche of patients with endometriosis has a distinct cellular profile. However, the proposed genetic characterization experiments are not properly justified nor does the applicant describe how results from these experiments will be used to inform Aims 2 and 3. - Aim 2 is novel, well presented, and feasible. Principal Investigator - The applicant has a strong track record and is an established international expert in his/her area of expertise. This proposal represents a change in focus and though the applicant has not yet published in this field, there is little doubt that he/she could become expert in this field. - The applicant does present a comprehensive career development plan, but the career goals are not clearly demarcated, and it is not clear what the split would be between clinical and research work. - A major weakness of the career plan is that the applicant does not clearly describe how he/she will take advantage of the environment to develop additional skills that will facilitate clinical research. - The applicant has chosen appropriate and experienced mentors, though he/she could have taken more advantage of the excellent mentors available at the institution in this area of expertise. Institutional Commitment - The institution has made a major commitment to the applicant’s career development as a physician scientist. - The institution is clearly committed to human stem cell research and has an outstanding track record in this area. - The environment is excellent for the conduct of the proposed research. Responsiveness - The application is generally responsive to the RFA, although reviewers expressed two concerns. First, the applicant has not definitely demonstrated that the described uterine epithelial stem cell population is truly a stem cell or progenitor population, and responsiveness hinges on this data. Second, the applicant is established as an independent scientist, and although funding this proposal would promote a change of scope of the applicant’s research, it is not entirely necessary to advance the applicant’s career development as a physician scientist. Hence, the candidate himself/herself is not highly responsive to the objective of the RFA.

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