Both Types 1 and 2 diabetes result from reductions in pancreatic beta cell mass and function. Thus, a major goal of the NIH/NIDDK is to develop novel drugs and tools that can lead to replacement and/or regeneration of human beta cells. This is has proven difficult, because adult human beta cells are refractory to engagement in cell cycle progression. Recently, we designed and performed a unique high-throughput screen (HTS) of two small molecule libraries, a 2000 compound FDA library and a second 100,000 compound library, and have identified a novel and effective small molecule, harmine, that is able to activate mouse, rat and human beta cell replication at rates that approach those required for therapeutic human beta cell replication. We have also identified additional compounds that share structural and functional features with harmine, and refer to them as harmalogs. Ongoing structure-activity studies suggest that the common pathway employed by these compounds is a calcineurin-NFaT-DYRK1A pathway, but additional pathways and intracellular targets remain possible. As for the broad field of beta cell biology in general, targeting harmalogs to beta cells is challenging. Accordingly, in this application, we assemble a team of experienced beta cell biologists and medicinal chemists to pursue three Specific Aims: 1. To Fully Define the Mechanism of Action of the Harmalogs on Human Beta Cell Proliferation. 2. To Document In Vivo Effects of the Harmalogs on Human Beta Cell Expansion and Function. 3. To Synthesize Modified Harmalogs with Chemical Linkers That Allow Both Retention of Bioactivity and Conjugation to Beta Cell-Targeting Ligands. We believe these studies are highly significant because they document that adult human beta cells can be induced to proliferate at therapeutically relevant rates using small molecule approaches; they will define the molecular mechanism of action of the harmalog class of compounds; and, because they explore novel methodologies to target these effective regenerative compounds to the human beta cell.
In this proposal, we will more fully define the mechanism of action of the harmalog class of compounds, will assess their ability to drive human beta cell expansion using in vivo models, and will initiate strategies to specifically direct harmalogs to th human beta cell. These studies are directly relevant to the 2.5 million people in the US with T1DM, the 25 million with T2DM, and the 330 million people globally with diabetes, all of whom will benefit from therapeutic approaches to expand beta cell mass and function.
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