Rescue of Pituitary Function in a Mouse Model of Isolate Growth Hormone Deficiency Type II by RNAi

James Patton, Professor, Vanderbilt University

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Launch presentation

About the speaker

Name: James Gerard Patton

Birth: June 13, 1958 Adrian, Michigan

Address: Department of Biological Sciences
Vanderbilt University
Box 1820 Station B
Nashville, TN 37235

Phone: 615-322-4738 or 615-343-6707 (FAX)
E-Mail: James.G.Patton@Vanderbilt.edu

Education/Training
1976-1980 B.A., Chemistry
College of St. Thomas, St. Paul, Minnesota

1983-1988 Ph.D., Molecular Biology and Biochemistry
Mayo Clinic, Rochester, Minnesota

1988-1992 Post-Doctoral Fellow, Harvard Medical School

Research Employment
1980-1983 Atherosclerosis Research Unit, Mayo Clinic, Rochester, MN

1988-1992 Post-doctoral Fellow
Department of Molecular and Cellular Physiology, Harvard Medical School
Department of Cardiology, Children's Hospital, Boston, MA

1993-1999 Assistant Professor
1999-present Associate Professor
2005-present Professor
Department of Biological Sciences, Vanderbilt University
2000-present Director, Interdisciplinary Graduate Program
Vanderbilt University

Current Funding
RO1 GM62487 Patton (PI) 8/01/02-1/31/09
NIH/NIGMS $180,000 direct costs
Mechanisms and Regulation of Alternative pre-mRNA Splicing
Role: PI

RO1 DK35592 Phillips (PI) 4/1/05--3/31/10
NIH/NIDDK $255,000 direct costs
GH Alternative Splicing: Mechanisms and Diseases
Role: Co-Investigator (John Phillips, PI)

RO1 GM 075790-01 Patton (PI) 7/01/05-6/31/09
NIH/NIGMS $195,000 direct costs
Identification and Characterization of Zebrafish microRNAs.
Role: PI

5 T32 GM008554-08 Patton (PI) 7/01/06-6/30/11
NIH/NIGMS $385,695 direct costs
Cellular, Biochemical, and Molecular Sciences Training Grant

Pending
2RO1 GM075790-05 Patton (PI) 7/1/09-6/31/14
NIH/NIGMS $250,000 direct costs
Identification and Functional Characterization of Zebrafish miRNAs

1R21EY019759 Patton (PI) 7/1/09
NIH/NIE R21 Proposal
Analysis of miRNA Function During Eye Development and Retinal Regeneration

Research Interests
Our lab focuses on the role of RNA in the regulation of gene expression. This encompasses three main projects. The first is to understand the mechanisms and regulation of alternative pre-mRNA splicing. The is especially important given that the majority of genes in higher eukaryotic organisms are subject to tissue-, cell-, and developmental-specific splicing. Currently, our work has centered on the human growth hormone gene where aberrant exon skipping leads to growth hormone deficiency, small stature, and anterior pituitary hypoplasia.
A second area of research is devoted to understanding microRNA (miRNA) function during early vertebrate development using zebrafish as a model organism. We seek to determine how many miRNAs are encoded in vertebrate genomes, identify the target genes regulated by these miRNAs, and understand how overall gene expression is regulated by miRNAs.
The third project combines our expertise in both small RNAs and splicing through the use of siRNAs to selectively and specifically destroy transcripts encoding a dominant negative form of human growth hormone. We have shown that genetic delivery of such siRNAs can rescue a form of growth hormone deficiency leading to our most recent work devoted to non-genetic delivery of siRNAs to treat disease.

Abstract

Mutations in the human growth hormone (hGH) gene (GH-1) in and around exon 3 can cause exon skipping of resulting in a form of growth hormone deficiency termed Isolated Growth Hormone Deficiency type II (IGHD II). The GH-1 gene contains 5 exons; constitutive splicing produces the wild type 22kDa hormone while skipping of exon 3 results in transcripts encoding a 17.5 kDa isoform that acts as a dominant negative to block secretion of the wild type hormone. Common characteristics of IGHD II include short stature due to delayed skeletal maturation, delayed puberty and, in severe cases, anterior pituitary hypoplasia. Current treatment of IGHD II involves delivery of recombinant growth hormone which can effectively rescue stature defects but does not prevent progressive pan-pituitary defects due to hypoplasia and inflammation. Here, we have used delivery of short hairpin RNAs (shRNAs) to rescue a murine model of IGHD II by specifically targeting transcripts encoding the dominant negative 17.5 kDa isoform.

Launch presentation