Our laboratory has previously demonstrated that cell-matrix adhesion receptors of the Integrin family are important regulators of islet progenitor cell adhesion, migration and differentiation. More recently, we have discovered that ablation of ?1 integrin in developing pancreatic ?-cells causes a dramatic reduction of the number of ?-cells by negatively regulating the expression of genes promoting cell cycle progression. Building on these recent discoveries, in this proposal our goal is to study the role of downstream effectors of ?1 integrin signaling that may be required for proper ?-cell mass development. Among signaling molecules recruited by ?1 integrins upon binding to their ECM ligands, ILK (integrin-linked kinase) is of significant interest due to its involvement in multiple developmental processes encompassing cell migration, proliferation, differentiation and cell survival. Hence, to investigate the possible role of ILK in ?-cell development and function our experimental strategy will focus on the following studies. In a first series of experiments (Aim 1), we will breed Ins1Cre mice to ILKflox/flox mice to generate Ins1Cre/ILK-/- animals and thus achieve constitutive deletion of ILK in ?-cells during embryonic life. These experiments will determine the requirement of ILK in ?-cell development and function. In a second set of experiments (Aim 2), we will conditionally delete the floxed ILK allele in ?-cells during the first two weeks of postnatal life by crossing tamoxifen-inducible Ins1CreERT2 knock-in mice with ILKflox/flox mice to generate Ins1CreERT2/ILK-/- animals. The importance of these studies resides in the ability to conditionally ablate ILK during a select time window of postnatal life when the most significant expansion of ?-cells is known to occur. Finally, (Aim 3) to gain knowledge on the possible involvement of ILK in processes of adaptive ?-cell homeostasis and regeneration, we will test the ability of either Ins1Cre/ILK-/- or Ins1CreERT2/ILK-/- animals to compensate metabolic demands following the exposure to metabolic stressors such as high fat diet, and to regenerate following ?-cell injury by streptozotocin. Based on the known signaling properties of ILK in other cell types, we anticipate that the proposed studies will uncover novel mechanisms of islet cell neogenesis, growth and differentiation, and may ultimately contribute to the identification of novel druggable targets that promote ?-cell development, expansion, survival and/or regeneration.
Over the past two decades, we and others have demonstrated that cellular receptors of the integrin family mediating interactions with the extracellular matrix (ECM) are essential to proper pancreatic islet cell development and secretory function. In this project we propose to identify the in vivo function of the integrin- linked kinase (ILK), a downstream effector of ?1 integrin signaling function, in the developing pancreatic epithelium. Specifically, our project focuses on defining the function(s) of ILK in pancreatic ?-cells, both during development and in postnatal life. Results from these studies have significant translational implications for the future development of drugs that can modulate the activity of downstream effectors of ECM/integrin signaling such as ILK, and lead to the development of pharmacological strategies for the induction of ?-cell expansion and/or regeneration from pancreatic progenitors in diabetes.
|Abebe, Tsehay; Mahadevan, Jana; Bogachus, Lindsey et al. (2017) Nrf2/antioxidant pathway mediates ? cell self-repair after damage by high-fat diet-induced oxidative stress. JCI Insight 2:|
|Mussar, Kristin; Pardike, Stephanie; Hohl, Tobias M et al. (2017) A CCR2+ myeloid cell niche required for pancreatic ? cell growth. JCI Insight 2:|
|Jimenez-Caliani, Antonio J; Pillich, Rudolf; Yang, Wendy et al. (2017) ?E-Catenin Is a Positive Regulator of Pancreatic Islet Cell Lineage Differentiation. Cell Rep 20:1295-1306|