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Dr. Andrew C. Karaplis
Senior Investigator, Lady Davis Institute 
Professor of Medicine, McGill University
Attending Physician, Division of Endocrinology, Jewish General Hospital
Director, Metabolic Bone Disease & Post-Fracture Clinics, Jewish General Hospital
Dr. Karaplis aspires to bridge the gap between basic molecular investigation and clinical practice. Investigative endocrinology remains one of the most fertile areas of interchange between basic research and clinical medicine. The vital role endocrinology has played in the advancement of clinical/biomedical science is clearly exemplified by the stellar academic character and enormous productivity of the Endocrinology Division at McGill University. Among his principal objectives has been to provide his M.D. and Ph.D. trainees with a thorough grounding in the basic principles of biomedical investigation, including careful analysis of the biological problem under investigation, thoughtful design of the experimental approach, experience with a rigorous research methodology, and careful interpretation of data while emphasizing an imaginative research approach and strong sense of commitment. Under his guidance, M.D. trainees with a strong disease-oriented perspective, receive broad training in the latest methods of basic research, while Ph.D. trainees acquire a strong clinical imprint along with their research training. Hence, a pivotal objective in his career plans has been to encourage trainees to seek, whenever appropriate or possible, practical applications of their research findings toward ultimate improvements to patient care.

At the same time, he is personally committed to patient care and the practical aspects of clinical investigation aimed at improved understanding of pathophysiology of disease and its treatment. He strives to become an active and productive clinician-scientist, and a cherished teacher, centrally placed within the governing structure of the research and clinical community at McGill, the Lady Davis Institute for Medical Research, and the Jewish General Hospital. He aims to continue demonstrating his commitment to clinical and basic research which has characterized his career over the past twenty years, while nurturing and training junior faculty, fellows and students, enabling them to develop into mature, broadly-competent and independent scholars.

Major Research Activities
Dr. Karaplis' "Lethal chondrodysplasia from targeted disruption of parathyroid hormone-related peptide gene" (Genes & Development, 1994) is a landmark study in the field. This work established, unequivocally, a pivotal role for the protein in skeletal development. The impact of this study is reflected in the number of subsequent publications from his group, as well as others, addressing various aspects of PTHrP action in bone. For this work, he was awarded the Young Investigator Award from the American Society for Bone & Mineral Research (ASBMR) and the Outstanding Investigator Award in the Bone Field from the International Bone and Calcium Institute.
His generation of the PTHrP- and PTH/PTHrP-null mice has had much broader implications than originally anticipated. These animals have: (i) served as a unique model for studying transplacental calcium transport and fetal/maternal calcium homeostasis (Proc Natl Acad Sci USA, 1996), (ii) demonstrated the essential role PTHrP plays in mammary gland development (Dev Biol 1998), lactation (J Clin Invest, 2003) and tooth eruption (Proc Natl Acad Sci USA, 1998) (iii) provided the impetus for identifying human skeletal disorders arising from abnormal PTHrP signaling in bone.

The manuscript "Nucleolar localization of PTHrP enhances survival of chondrocytes under conditions that promote apoptotic cell death” (Mol Cell Biol 1995) was groundbreaking as it put forth the concept that the capacity of PTHrP to influence normal cellular function should also be considered in terms of its effects at the level of the nucleus. Dr. Karaplis' team characterized nuclear PTHrP forms and reported that these peptides arise from initiation of translation at alternate, internal codons (
Endocrinology 2001). This constituted the first example of translation initiation at downstream non-AUG codons in a mammalian protein. More recently, he consolidated a physiologic role for nuclear PTHrP signaling by addressing this question in a relevant setting, that is, the intact organism. This in vivo approach required the generation of a mouse with a strategically placed mutation in the PTHrP gene so that signaling through the cell surface receptor would be maintained although it would not be compatible with the generation of nuclear PTHrP forms. Mice homozygous for the knock-in mutation displayed retarded growth and early senescence leading postnatally to their rapid demise. Decreased cellular proliferative capacity and increased apoptosis in multiple tissues were associated with altered expression and subcellular distribution of the senescence-associated tumor suppressor proteins and oncogenes. These findings established a pivotal role for nuclear PTHrP in promoting cellular proliferation while inhibiting pathways leading to senescence (Proc Natl Acad Sci USA, 2008).

Recent Publications

Bai X, Dinghong Q, Miao D, Goltzman D, Karaplis AC. Klotho ablation converts the biochemical and skeletal alterations in FGF23 (R176Q) transgenic mice to a Klotho-deficient phenotype. Am J Physiol Endocrinol Metab 2009;296:E79-E88.

Panda D, Goltzman D, Juppner H, Karaplis AC. TIP39/Parathyroid hormone type 2 receptor signaling is a potent inhibitor of chondrocyte proliferation and differentiation. Am J Physiol Endocrinol Metab 2009;297:E1125–E1136.

Sun W, Sun W, Liu J, Zhou X, Xiao Y, Karaplis AC, Pollak MR, Brown E, Goltzman D, Miao D. Alterations in phosphorus, calcium and PTHrP contribute to defects in dental and dental alveolar bone formation in calcium-sensing receptor-deficient mice. Development 2010;137:985-992.

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