? The goal of this Mid-Career Investigator Award in patient-oriented research (POR) is to expand research and training in inherited metabolic liver diseases (IMLDs), using Gaucher disease (GD) and Wilson disease as index diseases at Yale School of Medicine. The candidate Pramod K. Mistry, MB BS, PhD., an Associate Professor of Medicine, is a respected clinical investigator with unique training and research experience in GD. This proposal will enable Dr. Mistry to expand his current research efforts and to develop a mentoring program that focuses on IMLDs at Yale's Liver Center integrating clinical, laboratory, genetic and epidemiologic approaches. ? The proposed research project is a continuation of Dr Mistry's ongoing POR.
Specific aims are: 1. To explore the contribution of genetic variation in macrophage responsiveness to variation of disease severity in GD in N370S homozygous patients. The proposal seeks to investigate association of disease severity with functional polymorphisms in genes encoding the cytokines that are elevated in GD: Macrophage migration inhibitory factor (MIF), IL 6, IL 10, TNF alpha and TGF beta. 2. To evaluate two further candidate modifier genes for their contribution to a specific phenotype of type 1 GD/severe pulmonary hypertension. Thus, type 1 GD patients with severe PH will be examined for mutations in components of TGF-beta signaling pathway: BMPRII (bone morphogenetic protein receptor II) and ALK1 (activin receptor-like kinase 1). ? The goals of the mentorship program are to develop scholarship and technical skills in trainees to conduct meritorious POR in IMLDs. The training program consists of a core curriculum, an individualized didactic component in methods of clinical and translational research and an intensively supervised research project in POR. This training program is supported by Liver T32 DK 07356. ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Midcareer Investigator Award in Patient-Oriented Research (K24)
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Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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Vilarinho, Sílvia; Choi, Murim; Jain, Dhanpat et al. (2014) Individual exome analysis in diagnosis and management of paediatric liver failure of indeterminate aetiology. J Hepatol 61:1056-63
Mistry, Pramod K; Liu, Jun; Sun, Li et al. (2014) Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease. Proc Natl Acad Sci U S A 111:4934-9
Mistry, Pramod K; Taddei, Tamar; vom Dahl, Stephan et al. (2013) Gaucher disease and malignancy: a model for cancer pathogenesis in an inborn error of metabolism. Crit Rev Oncog 18:235-46
Yuen, Tony; Iqbal, Jameel; Zhu, Ling-Ling et al. (2012) Disease-drug pairs revealed by computational genomic connectivity mapping on GBA1 deficient, Gaucher disease mice. Biochem Biophys Res Commun 422:573-7
Liu, Jun; Halene, Stephanie; Yang, Mei et al. (2012) Gaucher disease gene GBA functions in immune regulation. Proc Natl Acad Sci U S A 109:10018-23
Zhang, Clarence K; Stein, Philip B; Liu, Jun et al. (2012) Genome-wide association study of N370S homozygous Gaucher disease reveals the candidacy of CLN8 gene as a genetic modifier contributing to extreme phenotypic variation. Am J Hematol 87:377-83
Lo, Sarah M; Choi, Murim; Liu, Jun et al. (2012) Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis. Blood 119:4731-40
Mistry, Pramod K; Weinreb, Neal J; Kaplan, Paige et al. (2011) Osteopenia in Gaucher disease develops early in life: response to imiglucerase enzyme therapy in children, adolescents and adults. Blood Cells Mol Dis 46:66-72
Stein, Philip; Yang, Ruhua; Liu, Jun et al. (2011) Evaluation of high density lipoprotein as a circulating biomarker of Gaucher disease activity. J Inherit Metab Dis 34:429-37
Nagral, A; Mewawalla, P; Jagadeesh, S et al. (2011) Recombinant macrophage targeted enzyme replacement therapy for Gaucher disease in India. Indian Pediatr 48:779-84

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