The gradual loss of insulin-producing beta cells of the endocrine pancreas is common to all forms of diabetes. Elucidating transcriptional complexes that increase our understanding of underlying mechanisms governing pancreatic beta-cell development and function is critical for the development of novel therapeutics that will improve beta-cell function. Loss- and gain-of-function mouse studies have demonstrated critical roles of transcription factors in regulating the establishment and function of beta cells. Preliminary data from our lab and others suggest Lhx1, a LIM-homeodomain transcription factor, is expressed and functions in the developing and adult pancreas. Over the next three years, I propose to investigate in detail the role of Lhx1 in regulating beta-cell development and function using beta cell lines as well as a newly developed conditional knockout model. I hypothesize that Lhx1 is a regulator of endocrine cell development and function.
In Aim 1, I will characterize Lhx1 expression at specific developmental and postnatal stages.
In Aim 2, I will determine Lhx1 gene regulatory mechanisms in beta cells.
In Aim 3, I will characterize the effects of Lhx1 ablation in the developing and adult pancreas using pancreas-specific cre/lox knockout approaches.
Hyperglycemia results from beta cell loss, which if left untreated, leads to frank diabetes and serious secondary health complications. Diabetes Mellitus is a metabolic disorder characterized by either the gradual or absolute loss of insulin-producing pancreatic beta cells. Investigation of transcription factors and co- regulators that govern genes critical to beta cell development and function could lead to beta cell replacement therapies and identify novel drugs that will improve beta cell function.
