β cell replacement therapy : a novel application for targeted epigenetic editing / Kristy Ou.

Ou, Kristy, author.
Other Title:
Beta cell replacement therapy
[Philadelphia, Pennsylvania] : University of Pennsylvania, 2018.
vii, 109 leaves : illustrations ; 29 cm
Local subjects:
Penn dissertations -- Pharmacological sciences.
Pharmacological sciences -- Penn dissertations.
Pancreatic β cells are the exclusive source of insulin, which normalizes blood glucose levels under hyperglycemic conditions. In 2015, over 252,000 deaths in the United States were contributed by diabetes, a family of disorders directly linked to defects in the pancreatic β cells. β cell deficiency or dysfunction leads to insufficient insulin secretion, resulting in chronic hyperglycemia and increased risk for severe health complications. Although severely diabetic patients can clinically manage their glucose levels with mealtime delivery of insulin analogues, many still experience potentially life-threatening hypoglycemic episodes due to erroneous insulin administration. Only β cell replacement therapy, through the transplantation of deceased donor-derived pancreatic islets, can maintain long-term glycemic control without hypoglycemic episodes.While β cell replacement therapy is an extraordinary breakthrough for diabetes treatment, the scarcity of transplantable β cells prevents it from becoming a realistic therapeutic option. Generating transplantable β cells through expansion of pre-existing β cells remains challenging given that healthy, adult β cells are resistant to cell cycle entry. Elucidating pathways that promote β cell expansion in mouse models, such as during pregnancy or early diabetes, may identify exploitable pro-proliferative targets. However - as in the case with overexpressing ST5, an activator of the Ras/ERK/MAPK pathway - there are often challenges associated with dissecting the pro-proliferative and anti-proliferative signals in the β cell.Human genetic diseases distinguished by β cell hyperplasia can also allude to pro-proliferative therapeutic targets. Indeed, mimicking the epimutation underlying Beckwith-Wiedemann Syndrome, a congenital imprinting disorder characterized by massive β cell expansion, can stimulate β cell proliferation in adult human islets. In order to introduce the epimutation, a transcription activator-like effector protein fused to the catalytic domain of TET1 (TALE-TET1 fusion protein) was engineered to target and demethylate the Imprinting Control Region 2 in a locus specific manner. This demonstrates for the first time that epigenetic editing can be employed to promote β cell proliferation, which may one day provide additional sources of transplantable β cells in the future.
Department: Pharmacology.
Supervisor: Klaus H. Kaestner.
Ph. D. University of Pennsylvania 2018.
Includes bibliographical references.
Kaestner, Klaus H., degree supervisor.
Bartolomei, Marisa S., degree committee member.
Blobel, Gerd A., degree committee member.
Davies, Peter F., degree committee member.
Stoffers, Doris A., degree committee member.
University of Pennsylvania. Department of Pharmacology, degree granting institution.
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