sulin secretion from pancreatic beta-cells is critical for glucose homeostasis.When insulin secretion isimpaired, when beta-cell mass declines or when resistance to insulin occurs, diabetes results in one or more complex forms. Curiously, zinc deficiency is also a hallmark of all diabetic states. We hypothesize thatzinc signaling and recycling may be impaired in beta-cells during diabetes. We postulate that autocrineextracellular zinc and ATP signaling may occur within islet microenvironments and support pancreaticbeta-cell homeostasis. Preliminary work in beta-cells and islets supports these hypotheses. Taken together,we pose the central hypothesis that: Zinc and ATP are secreted by pancreatic beta-cells and haveessentialextracellular autocrine influence and intracellular effects on beta-cell homeostasis and function. Wepropose two specific aims. #1: Define the secretion or co-secretion of ATP and zinc with insulin in responseto glucose and other stimuli. #2: Examine autocrine supportive effects of zinc and ATP for beta-cells via membrane receptors and transporters. Lay Summary: Diabetes in its multiple forms is caused by loss offunction of the blood glucose-storing hormone, insulin. Zinc deficiency has also been linked to all forms ofdiabetes. Maneuvers or therapeutic targets that support, protect and/or augment pancreatic beta-cellfunction with zinc and/or ATP are sought to understand cytoprotective roles of of zinc for beta-cells and islet.PHS416-1 (Rev.06/02) Page 2 Number pages consecutively at thebottom throughout (Form Page 2) the application. Do not use suffixes such as 2a, 2b.Kirschstein-NRSA Individual Fellowship Application NAME OFAPPLICANTYUsf, first, middle initial) Williams, Clintoria, L. Table of Contents Page Numbers (Number pages consecutively at the bottom throughout theapplication.Section 1Applicant Do not use suffixes such as 6a, 6b.)Face Page (Items 1-8,15), Page 2 (Items 16-18, 22), and Table of Contents (Form Page 3)... 1 -3Scholastic Performance (Form Page 4) 4Background (Form Page 5) 5Research Experience (Form Page 6) a. Summary b. Doctoral Dissertation c. PublicationsRevised Application N/AResearch Training Plan a. Activities Under Award b. Research Training Proposal 10-19 (1) Specific Aims 10 (2) Background/Significance Jr (Not to exceed 10pages). 10-15 (3) ResearchDesign and Methods 15-19 (4) Literature Cited 20-23 (5) Human Subjects Research (Required if Item 9on theFace Page is marked 'Yes') N/A (6) Data and Safety Monitoring Plan (Requiredif Item 9contheFace Page is marked 'Yes' and aPhase I, II, or III clinical trialis proposed) N/A (7) Vertebrate Animals (Requiredif Item 10a on the Face Page is marked 'Yes') 24.25 c. Respective Contributions 25 d. Selection of Sponsor and Institution 25 e. Responsible Conduct of Research 25Section 2 SponsorBiographical Sketch (Form Page 7) 26-28Research and Training Support/Previous Trainees (Form Page 8) 29.30Facilities and Commitment Statement (Form Page 8) , 30-35 Training Plan, Environment, Research Facilities 30-35 Number of Fellows/Trainees to be Supervised 30-35 Applicant's Qualifications and Potential 30-35 Human Subjects , 35 Vertebrate Animals 35Checklist (Form Page 9) 36Section 3 References (Minimum of 3) (See instructions for submission of references.)List full name, institution, and department of individuals submitting reference letters. Isabella Finkelstein,Ph.D. Clark Atlanta University Department of Biological Sciences Shawn Galin,Ph.D. University of Alabama-Birmingham Department of Physiology and Biophysics Lisa Schwiebert,Ph.D. University of Alabama-Birmingham Department of Physiology and BiophysicsOther Items (list): Personal Data Page for Fellowship ApplicantsSection 4 Appendix / (3collatedsets. Nopage numbering necessary. Notto exceed 3publications; 2 for predoctoral candidates.) Check if Appendix is included Fi'J-~
