Kenneth Adolph

The focus of my research is on proteins that are involved in a variety of fundamental biological functions and that, when malfunctioning, can result in human diseases and disorders. In particular, my research at present is concentrated on the extracellular proteins called thrombospondin proteins. These proteins are involved in important biological activities that include blood vessel formation, immune function, cardiovascular function, wound healing, bone and collagen formation, musculoskeletal function, and nerve cell connections. If any of these are not acting normally, diseases and disorders can result that include tumor progression/metastasis, cardiovascular disease, abnormal skeletal development, osteoporosis, degenerative joint disease, and neurological disorders. Understanding how thrombospondin proteins act is crucial to developing therapies to cure or alleviate these abnormal conditions.

Research in my laboratory is currently focused on the thrombospondin proteins (TSPs). The thrombospondins (TSP1, 2, 3, 4, 5/COMP) are a family of large extracellular proteins with complex and characteristic protein domain structures. Through the protein domains, the thrombospondins interact with cells and extracellular proteins to mediate cell-extracellular matrix interactions and cell-cell interactions, as well as tissue remodeling, cell proliferation, and cell migration. Because of these interactions, roles for TSPs have been identified in a variety of fundamental biological functions. The roles include an involvement in angiogenesis, immune function, cardiovascular function, wound healing, collagen formation, bone formation, musculoskeletal function, and synaptogenesis. Due to these various fundamental roles, thrombospondin malfunction is an important factor in diseases and disorders that include tumor progression/metastasis, cardiovascular disease, skeletal dysplasia, osteoporosis, degenerative joint disease, and neurological disorders.

A particular research interest concerns the thrombospondin proteins of invertebrates. The aim is to investigate similarities and differences in the structure and function of invertebrate TSPs compared to vertebrate TSPs to more fully understand the roles of human TSPs. At present, there is no published information about the possible functions of invertebrate thrombospondins. It has been found in my research that TSPs are present in invertebrate phyla, including Mollusca, Cnidaria, Echinodermata, Arthropoda, and Chordata. In addition to TSPs that have similarities to vertebrate TSPs in their size (about 1100 amino acids), amino acid sequences, and protein domain structures, unique Mega-TSPs of about 2900 amino acids have been detected in a number of invertebrate species. Further, the presence of additional TSP-like proteins in invertebrates that show less resemblance to the canonical vertebrate TSPs (TSP1-5) complicates understanding of invertebrate TSP function. My studies of the various invertebrate and vertebrate TSPs are continuing.

Another interest is in the metaxin proteins. The metaxins (metaxins 1, 2, and 3) are a widely distributed group of proteins that are found in vertebrates and invertebrates. Metaxin-like proteins have also been detected in fungi, protists, plants, and bacteria. The metaxins and metaxin-like proteins are less complex than the thrombospondin proteins, with about 300 amino acids and only two major protein domains. In humans, roles for metaxins 1 and 2 have been implicated in the process of protein import into mitochondria. In connection with human disease, mutations in the metaxin 2 gene are associated with a premature aging syndrome (mandibuloacral dysplasia, or MAD), potentially due to mitochondrial dysfunction.