Request for Funding

Medical Student Research Fellowship for Summer 2002

Mentor: Ivor J. Benjamin, MD
Department: Internal Medicine/Molecular Cardiology
Room number: NB11.102
Mail Code: 8573
Phone number: x81405; x81634
E-mail: ivor.benjamin@utsouthwestern.edu
Project title:

Human subjects IRB approved project number (where applicable): N/A

Animal subjects IRB approved project number (where applicable): On file

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects)

Brief Description of Project:
Two interrelated lines of investigations command the primary interests of our laboratory.

1) Molecular Mechanisms of AlphaB-crystallinR120G familial cardiomyopathy. Most but not all heat shock proteins are molecular chaperones (Circ. Res. 83:117-132, 1998; J. Clin. Invest. 106: 2000), whose primary properties can prevent protein aggregation and unfolding (reviewed in Christians et al, Crit Care Med, 30: S43-50, 2002). The alphaB- crystallin (aBC) gene encodes a 22 kDa heat shock protein with chaperone-like properties and is abundantly expressed in striated cardiac and skeletal muscle. Studies of a French pedigree have established that a substitution mutant in the aB-crystallin protein (arginine at position 120 is replaced by glycine) causes an inheritable multisystem disorder including premature death from intractable congestive heart failure and lethal arrhythmias. Mutant aB-crystallinR120G protein and intermediate filament (IF) proteins (i.e., desmin) are deposited within electron dense aggregates in cardiac cells and tissues, which suggests that abnormal protein misfolding leads to proteotoxic damage and, perhaps, plays a central role in the pathogenesis of cardiomyopathy. Our primary goal is to develop small animal models using transgenic and gene knock-out mice, which mimic humans disease, as an experimental tool for molecular approaches aimed at understanding the basic mechanisms and, ultimately, designing novel interventions to reverse and ameliorate disease progression. A novel feature of this approach is that it permits us to test directly whether or not interventions with specific HSP chaperones can alter the phenotype of the aB-crystallinR120G cardiomyopathy in vivo.

2) How does the stress-response pathway controlled by heat shock transcription factor, HSF1, modulate pathophysiological arising from ischemia/reperfusion injury and heart failure in mice? Heat shock transcriptional factor 1 (HSF1) is the major regulator of hsp genes and controls rapid induction of stress protein genes in cells and organisms exposed to various environmental challenges such as pressure-overload hypertrophy and myocardial ischemia. Our laboratory first created Hsf1-/- knockout mice lacking stress-inducible synthesis of hsp gene expression. Although the Hsf1-/- knockout has a revealed a number of novel developmental requirements, the adult mice exhibit exaggerated proinflammatory cytokine TNFa production resulting in increased mortality after endotoxin challenge (JBC 273: 7523-7528, 1998; EMBO Journal 18: 5943-5952, 1999; (Nature, 407: 693-694, 2000). Furthermore, this robust model affords us the ability to test various hypotheses related to HSF1-dependent requirements for myocardial protection against ischemia/reperfusion, pressure-overload hypertrophy, and heart failure. A major gene discovery program using DNA microarray and proteomics is also underway to identify novel downstream targets as possible pharmacological targets of HSF1 activity and functions.

Previous Research Activities or Publications with Medical Students:
We welcome and have had several students with varying levels of prior research experiences before joining the lab.

Jake Doskocil Summer HS Student (99) Sophomore, Texas A & M
Neil Desai Summer HS Student (99) Sophomore, MIT
Kenny Youens Summer Medical Student (99) MS02, UTSW
Enrico Duru, PhD Postdoctoral Fellow (00) Postdoctoral Fellow
Patrice Connell, PhD Postdoctoral Fellow (2000-present) NRSA Postdoctoral Fellow
Li Liu, MD Postdoctoral Fellow (2000-present) Postdoctoral Fellow
Nancy Price, Ph.D. Postdoctoral Fellow (2001) Postdoctoral Fellow
Tonya Watkins SURF Program-2001
Hemali Shah Summer Research Student ('01) Junior, UT Austin

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