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Type I Diabetes Model in Zebrafish

Award Information

Department of Health and Human Services
Award ID:
Program Year/Program:
2009 / STTR
Agency Tracking Number:
Solicitation Year:
Solicitation Topic Code:
Solicitation Number:
Small Business Information
1120 15th Street, Ca-2105 Augusta, GA 30912-
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Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
Phase 1
Fiscal Year: 2009
Title: Type I Diabetes Model in Zebrafish
Agency: HHS
Contract: 1R41DK082060-01A1
Award Amount: $195,511.00


DESCRIPTION (provided by applicant): Worldwide diabetes is projected to reach epidemic proportions in the next 25 years, however, the prevalence of diabetes in the U.S., India, China, Russia, and Japan is already spiraling out of control. One promising th erapy for diabetic conditions linked to the functional or outright loss of insulin-producing cells (i.e. pancreatic beta cells) is simply replenishing them. Two main strategies are being developed: 1) Transplantation of beta cells (cell replacement), and 2 ) Stimulation of endogenous progenitor/adult stem cells (cellular regeneration). Combined with suppression of an autoimmune response which targets beta cells, such therapies could represent lasting cures. The ultimate goal of this project is to create a di abetes model in which genetic networks that regulate the regeneration of insulin-producing pancreatic beta cells in vertebrates can be elucidated. Because zebrafish have a remarkable capacity for cellular regeneration - and are amenable to forward genet ics - mutations can be identified which disrupt the regenerative process. Accordingly, we have adapted an inducible cellular ablation system, termed ZAP, toward the goal of creating new tools for the study of cellular regeneration in zebrafish. The ZAP sys tem can be targeted to any genetically definable cellular subtype and thereby model diseases linked to the loss of a particular cell type (e.g., Type I diabetes). The ZAP system is based on transgenic expression of a fusion protein between a pro-drug conve rting enzyme and a fluorescent reporter. The enzyme converts otherwise innocuous pro-drugs into cytotoxins, thus adding pro-drugs to the water induces ablation in multiple fish simultaneously. The reporter allows automated quantitative detection of the pre sence or absence of the targeted cell type. We have recently demonstrated two key findings using transgenic zebrafish expressing ZAPs specifically in beta cells: 1) ZAP-expressing beta cells can be specifically eliminated upon treatment with pro-drug, 2) U pon removal of pro-drug, beta cells are rapidly regenerated over the course of the next few days. Here we propose to create transgenic zebrafish expressing the ZAP system in beta cells. In Phase II efforts, these transgenic animals will be mutagenized and screened for those individuals in which this innate capacity for beta cell regeneration has been disrupted. These mutant lines will provide unique insights into the genetic circuitry underlying the regulation of beta cell regeneration and may be utilized i n downstream commercialization efforts for the efficient screening and identification of compounds which stimulate progenitor/stem cells to replace lost beta cells. The specific aims of this proposal are: 1) The creation of transgenic lines that will facil itate ratiometric automated detection of targeted (beta) and control cells (alpha), and 2) Optimization and scaling of quantitative automated detection methods. PUBLIC HEALTH RELEVANCE: The number of people diagnosed with diabetes will reach epidemic propo rtions worldwide within the first quarter of this century. Therapies aimed at replacing or amplifying the number of insulin-producing cells in the body (the beta cells of the pancreas) show great promise for diabetic conditions which require daily insuli n injections. This study proposes to create a series of diabetic disease model organisms. Future studies will utilize these models to identify the genetic networks that regulate the process of beta cell regeneration. Insights gained from generating a diabe tes model will help indentify drugs capable of safely stimulating the production of new insulin-producing beta cells - a potential cure for this debilitating disease.

Principal Investigator:

Meera T. Saxena

Business Contact:

Tiongson M. Saxena
Small Business Information at Submission:

LUMINOMICS, INC. 1120 15th Street, Ca-2105 Augusta, GA 30912

EIN/Tax ID: 421577463
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
Research Institution Information:
SOM Office of Research Administration
Broadway Research Building Suite 117
RI Type: Nonprofit college or university