Pancreatic beta cells within the Islets of Langerhans are required for glucose-stimulated insulin secretion and glucose homeostasis. Dysfunction in beta cell activity or survival results in diabetes mellitus, a disease currently affecting millionsof Americans with numbers expected to greatly increase in the future, thus creating an enormous economic and health burden. A future strategy to improve outcomes for the growing numbers of diabetic patients requires understanding the complex developmental programs that specify and differentiate functional beta cells from progenitors. Exploiting existing knowledge and future understanding of the signaling and transcriptional events central to beta-cell biology will allow u to produce therapeutic replacement beta cells for transplantation. Central to these Aims is the hypothesis that the important cofactor, Ldb1, is required for the transcriptional processes mediated by LIM-domain transcription factors to produce functional beta cells during development and in adults. My preliminary data defines the expression pattern of Ldb1 in the pancreas as well as the role of Ldb1 in developing endocrine cells. Conditionally deleted mice demonstrated that Ldb1 developmental function partially overlaps with the only well-studied LIM factor in the pancreas, Islet-1 (Isl1).
These Aims will further define the Isl1-dependent and -independent genetic events controlled by Ldb1.
Aim 1 will utilize genome-wide microarray and ChIP-Seq approaches to elucidate the genes and pathways regulated in Ldb1 mutant mice that correlate with the observed phenotype.
Aim 2 will test the in vivo role of Ldb1-interacting co-regulators and I will also utilize an innovative immunoprecipitation procedure to isolate new Ldb1-interacting factors from beta cell lines, as I hypothesize that Ldb1 has unique interacting factors in the pancreas as compared to other tissues. Interesting new binding proteins will be tested for their role in Ldb1-mediated transcriptional control.
Aim 3 will utilize animals lacking Ldb1 specifically in adult beta cells to define the roles of Ldb1 in adult islet function and targe gene control and determine the link with Isl1 and other known and newly identified interacting proteins tested in Aim 2. With this K01 Career Developmental Award, I will test my overall hypothesis that Ldb1 is required for all LIM complexes functioning in developing and adult islet cells. My current environment is uniquely suited for me to successfully initiate the proposed studies and complete my postdoctoral training. I will develop the tools and skills to answer many of the questions raised by these Aims and generate interesting data allowing me to transition into funding as an independent investigator.
To combat the ever-growing health and economic costs associated with diabetes; sustainable and innovative treatments must be developed that improve quality of life for patients. One possibility involves novel cell-based transplantation therapies that must exploit current and future knowledge of the developmental processes and genetic programs to produce functional pancreatic beta cells from progenitors. The studies herein aim to define the importance of a critical cofactor; Ldb1; in controlling genes governing the development and mature adult function of insulin producing beta cells.
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