In skin epidermis, cell migration and basement membrane assembly and organization are central to many biological and pathological processes, including hair follicle morphogenesis, wound healing and cancer metastasis. Basement membranes (BM) are composed of ordered arrays of characteristic extracellular matrix proteins and both the epidermis and the dermis contribute to the synthesis of basement membrane components. While important roles of basement membrane during development, such as establishing cellular polarity, promoting cell adhesion and cell survival have recently been elucidated, less is known about the dynamics of basement membrane assembly in normal tissue homeostasis. Recent genetic and cell-biological studies underscore the importance of the integrin cell adhesion receptors in basement membrane assembly and tissue architecture, contributing to the proper balance and spatial arrangement of growth and differentiation in the epidermis. Our research so far has clearly demonstrated a role for a?1 containing integrins in basement membrane assembly. This proposed research addresses the interesting questions that have emerged, including: """"""""What are the integrin-mediated signals that are important to maintain BM integrity in vivo?"""""""" and """"""""What domains of the integrin molecule are critical for this signaling?"""""""" In this proposal we outline specific experiments to begin to understand how integrins, and their downstream signaling effectors regulate the process of basement membrane assembly/organization. Understanding the molecular mechanisms of individual integrin pairs is important not only in the context of normal tissue homeostasis but may also play a role in understanding how tumor cells are able to disrupt the BM and metastasize. Mammalian epidermis requires an intact """"""""basement membrane"""""""" which is critical for normal physiological function and development. Loss of basement membrane integrity is associated with devastating skin diseases and metastatic skin cancers. This research, which seeks to advance our knowledge of the critical role that Integrins (special proteins found in the cell membranes of epithelial cells) play in regulating and maintaining a dynamic yet intact basement membrane, will help identify specific molecular entities that may be associated with diseases and their treatments.
|Bandyopadhyay, Aditi; Rothschild, Gerson; Kim, Sean et al. (2012) Functional differences between kindlin-1 and kindlin-2 in keratinocytes. J Cell Sci 125:2172-84|
|Chen, B; Goodman, E; Lu, Z et al. (2009) Function of beta1 integrin in oral epithelia and tooth bud morphogenesis. J Dent Res 88:539-44|
|Bandyopadhyay, A; Raghavan, S (2009) Defining the role of integrin alphavbeta6 in cancer. Curr Drug Targets 10:645-52|