Slots: 1
Deadlines
Internal Deadline: Friday, May 17, 2024, 5pm PT
LOI: June 17, 2024
External Deadline: July 17, 2024
Award Information
Award Type: Grant
Estimated Number of Awards: 5
Anticipated Award Amount: Application budgets are limited to $750,000 direct costs per year. Equipment costs (only allowed for first year) and indirect costs on subcontracts are not included in the $750,000 direct cost cap. Equipment requests are capped at $100,000 and may be limited by available funds. It is anticipated that the award budget will be directly correlated to the breadth, quality and relevance to Cystic Fibrosis of the research base being served by the Center.
Who May Serve as PI: Because a Cystic Fibrosis Research Center has a large and complex administrative structure, the PD/PI must have strong leadership abilities and demonstrated proficiency in managing large, multi-component programs. In addition, the PD/PI should be a recognized leader and authority in the CF research community. The PD/PI must be willing to participate in meetings of the CF Center Directors which are scheduled in years 2 and 4 of the grant.
Link to Award: https://grants.nih.gov/grants/guide/rfa-files/RFA-DK-25-010.html
Process for Limited Submissions
PIs must submit their application as a Limited Submission through the Research Initiatives and Infrastructure (RII) Application Portal: https://rii.usc.edu/oor-portal/. Use the template provided here: RII Limited Submission Applicant Template
Materials to submit include:
- (1) Two-Page Proposal Summary (1” margins; single-spaced; standard font type, e.g. Arial, Helvetica, Times New Roman, or Georgia typeface; font size: 11 pt). Page limit includes references and illustrations. Pages that exceed the 2-page limit will be excluded from review. You must use the template linked above.
- (2) CV – (5 pages maximum)
Note: The portal requires information about the PIs in addition to department and contact information, including the 10-digit USC ID#, Gender, and Ethnicity. Please have this material prepared before beginning this application.
Purpose
Cystic Fibrosis is one of the most common, life-limiting genetic diseases, and is estimated to affect 30,000 Americans. Individuals with CF have inherited two mutated copies of the gene, cystic fibrosis transmembrane conductance regulator (CFTR), in every tissue of the body. Although lung disease is the primary cause of death in CF, multiple other organ systems have altered functions including the liver, pancreas, bone, sweat glands, and gastrointestinal and reproductive systems.
More effective management of the pancreatic complications and the lung infections has extended median survival in the United States to over 40 years of age. All states in the U.S. now screen for CF at birth to enable presymptomatic support for nutrition and preventing infections that may further improve the quality of life for these patients. Children identified at birth avoid the malnutrition that was the common presenting sign for CF. In addition, these patients benefit from many new forms of therapy that are being developed, including highly effective modulator therapies (HEMT), to aggressively eradicate bacterial colonization of the lung, control inflammation and lung damage, improve management of diabetes and liver disease and provide nutritional support.
In addition to treating the signs, symptoms and complications of CF, researchers are investigating molecular and pharmacologic methods to treat the underlying cause of CF. Screening of small molecules has identified lead molecules that increase either expression, processing, trafficking or function of the CFTR protein. This approach has led to the development of the drug ivacaftor which is approved for patients with the G551D substitution in CFTR as well as other mutations. A combination drug lumacaftor/ivacaftor was then approved for patients with the F508del mutation, the most common of the more than 2000 known CF mutations. Another combination drug, ivacaftor/tezacaftor, was subsequently approved. Triple drug therapy (elexacaftor/ivacaftor/tezacaftor) was approved in 2019 and can be used by 90% of CF patients. The success of these drugs is spurring the development of additional drugs with more mutation targets and greater potency, and also targeting those patients who are not eligible for HEMT treatment. The ultimate goal is to have effective therapies for all patients with CF.
Despite current available therapies, CF related gastrointestinal and nutrition problems remain. Although pancreatic enzyme replacement provides therapeutic benefit, the effects are variable and malabsorption still remains an issue. Thus, better nutritional support and diet composition recommendations are needed. With HEMT therapy, reports of obesity and metabolic syndrome are now emerging, issues previously not observed in patients with CF.
Now that subjects with CF are living longer, there is an increased incidence of CF-related diabetes (CFRD). In fact, about 40% of patients with CF will develop diabetes by the age of 20. How mutated CFTR results in diabetes is still unclear. Recent guidelines developed by the Cystic Fibrosis Foundation and the American Diabetes Association suggest that all patients should be screened for the development of diabetes yearly by an oral glucose tolerance test starting at the age of 10. Insulin treatment of CF-related diabetes has been shown to improve survival and lung disease in patients with CF. How new CF drug treatments affect CFRD incidence and progression is not yet completely clear, but at least some patients appear to benefit.
Another increased CF morbidity, in part reflecting the longer CF lifespan, is CF associated liver disease (CFLD) which can affect up to 30% of patients. Clinically there is great variability in presentation, from having asymptomatic liver enzyme elevations to frank cirrhosis. The mechanism(s) responsible for CF disease found in the liver and bile ducts is incompletely understood. Whether or not new CF drug treatment benefits CFLD is not yet known. CF related renal disease is also becoming more prevalent with longer lifespans.
Gene therapy approaches to deliver a normal CFTR gene are also being pursued. This approach would allow treatment options for those patients ineligible or unable to tolerate HEMT therapy. New vectors with less toxicity have been developed. A question is at what age should gene therapy be considered? The availability of improved animal models such as the pig and ferret, which better mimic the human disease, aid in the testing of these new therapies. These encouraging findings suggest that collaborative efforts between basic and clinical researchers could foster the translation of novel basic research findings into preclinical testing in animal models and potential clinical applications.
CF research often requires the use of specialized technologies and resources to support a cohesive research effort. The goal of the Center is to make state-of-the-art technologies and resources readily accessible to a broad spectrum of investigators working on CF.
Visit our Institutionally Limited Submission webpage for more updates and other announcements.