The laboratory's interests revolve around the cell and developmental biology of extracellular matrix. Our major focus is on acquisition of tissue-specific structure and function. These studies address fundamental questions regarding regulation of assembly and are relevant to connective tissues in general. We focus primarily on regulatory interactions involving matrix macromolecules as well as the influence of the fibroblast. We utilize mouse models and extend the work to human tissues as appropriate. While our focus is on the elucidation of the steps involved in tissue morphogenesis and growth, the questions also address repair/regeneration as well as dysfunctional regulation in connective tissue disorders. The laboratory has 2 major ongoing research projects addressing the regulation of extracellular matrix assembly in the tendon and cornea. Our general hypothesis is that extracellular matrix assembly is a multi-step process, with each step requiring specific regulatory interactions. The regulation of these steps is tissue-specific allowing for assembly of connective tissues with markedly different structures and functions, i.e., tendon and corneal stroma, from the same basic building blocks. Our work identified 3 key steps in extracellular matrix assembly; nucleation of fibril assembly; deposition and stabilization of immature fibril intermediates as well as their entrance into the growth phase; and linear and lateral fibril growth, generating the mature fibrils required for tissue function. We hypothesize that the regulation of these steps involve: heterotypic type V/XI collagen interactions with type I collagen; changing interactions with FACIT collagen types XII and XIV; and interactions with small leucine-rich proteoglycans (SLRPs) involving 2 SLRP classes, decorin and biglycan; and lumican and fibromodulin. We analyze mice with single or compound deficiencies at different stages during development using ultrastructural and morphometric approaches. We have developed conditional mutations to extend this work. These approaches are integrated with biochemical, immunochemical, molecular and biomechanical analyses to define specific functional interactions. In addition, my laboratory has a long term interest in the role of the cell in defining micro-domains to sequester the different regulatory interactions. Definition of the regulatory steps in tissue-specific matrix assembly provides a foundation to further the understanding of tissue repair/regeneration, aging and pathological changes as well as the modulation of these processes. In addition, my laboratory is involved in a number of productive collaborations. We collaborate with the bioengineering group at the University of Pennsylvania analyzing the injury response in tendons and the effects of aging. We also have collaborations addressing the roles of macromolecular processing in matrix assembly. These collaborations provide additional breadth to our major research focus.