molysis bullosa simplex (EBS) and epidermolytic 
hyperkeratosis (EH), in which patients have point 
mutations in genes encoding keratins, the major 
structural proteins of the epidermis; 2) engineered 
the animal models for these diseases that were fun- 
damental in elucidating the bases for human EBS and 
EH; 3) engineered deletions and point mutations in 
the basal epidermal keratins and examined their be- 
havior, leading to a correlation between the severity 
of EBS and the severity with which a specific muta- 
tion causes perturbations in keratin filament struc- 
ture; 4) identified sequences and transcription fac- 
tors necessary for gene expression in keratinocytes 
in vitro and in transgenic mice, leading to the devel- 
opment of an expression vector that can target ex- 
pression of genes to the epidermis of transgenic 
mice; and 5) shown that TGF-a (transforming 
growth factor-a), IL-6 (interIeukin-6), and TNF-a 
(tumor necrosis factor-a) play roles in controlling 
growth and differentiation in epidermal cultures 
and in transgenic mice that provide important ani- 
mal models for investigating the mechanisms under- 
lying the early stages of skin carcinogenesis and 
psoriasis. 
Mechanical forces are generated during several 
processes essential to life, e.g., in the musculoskele- 
tal system during locomotion, the uterus during par- 
turition, the lung during respiration, and the cardio- 
vascular system during circulation. The laboratory 
of Assistant Investigator Jeffrey F. Bonadio, M.D. 
(University of Michigan) has investigated the basis 
of load bearing in the mammalian skeleton and, in 
particular, has focused on the role of type I collagen 
and fibrillin in this process. In the course of these 
studies this group also identified a rational treat- 
ment strategy for skeletal fragility and degeneration 
in the general population, based partly on the regu- 
lation of collagen gene expression. The laboratory 
plans to test the validity of this strategy in animal 
model systems. Toward this end, the laboratory has 
discovered a novel method for transferring therapeu- 
tic genes to the cells of skeletal tissues, e.g., tendon, 
ligament, cartilage, and bone. 
The endothelins are a family of small peptide hor- 
mones with a variety of potent biological activities. 
The first member of the family was identified earlier 
by Associate Investigator Masashi Yanagisawa, M.D., 
Ph.D. (University of Texas Southwestern Medical 
Center at Dallas) and his colleagues as a strong 
blood pressure-raising molecule secreted by the 
cells lining the inner surface of blood vessels (the 
endothelium). This year, Dr. Yanagisawa's labora- 
tory has initiated two major projects aimed at further 
characterization of the physiological role and regu- 
lation of the endothelins and their receptors. These 
projects should lead to production and characteriza- 
tion of mice deficient for genes encoding the molec- 
ular components of the system and to molecular 
identification of a key enzyme in the biosynthesis 
pathway of the active peptides, the endothelin- 
converting enzyme. 
The studies in the laboratory of Investigator Joel F. 
Habener, M.D. (Massachusetts General Hospital) are 
directed toward the cellular mechanisms responsi- 
ble for the cell-specific expression and metabolic 
regulation of genes encoding polypeptide hor- 
mones. The group hypothesizes that interactions of 
DNA sequence elements and DNA-binding proteins 
occur in a combinatorial process to provide unique 
complexes resulting in the activation of transcrip- 
tion of specific genes in phenotypically distinct 
cells. The studies currently concern the cell- 
specific and cAMP-mediated activation of the so- 
matostatin and glucagon genes and the cell-specific 
expression of the angiotensinogen gene in the liver. 
The group seeks to isolate and characterize struc- 
turally cAMP-responsive DNA-binding phosphopro- 
teins and developmentally cell-specific homeo- 
domain proteins and to dissect the molecular 
interactions of the proteins with the specific DNA 
sequence elements and other components of the 
transcriptional machinery. 
The purpose of the research program of Senior 
Investigator Donald F. Steiner, M.D. (University of 
Chicago) and his colleagues is to gain a more com- 
plete understanding of the genetic and molecular 
mechanisms that underlie the production and ac- 
tions of insulin and related hormones of the pancre- 
atic islets of Langerhans. The biological functions of 
neuroendocrine precursor peptides, as exemplified 
by proinsulin, proglucagon, pro-IAPP (islet amyloid 
polypeptide), and/or the insulin receptor precur- 
sor, and the cell biological and biochemical mecha- 
nisms that lead to their proteolytic processing into 
active hormones, neuropeptides, or receptor mole- 
cules are also being intensively studied. The long- 
term goal is to develop basic molecular insight into 
the mechanisms regulating the development, 
growth, and function of the pancreatic islets and 
thereby eventually to develop new diagnostic and 
therapeutic approaches to metabolic disorders such 
as diabetes mellitus. 
Insulin is secreted when a fasting animal is given a 
glucose load. Insulin activates enzymes that pro- 
mote energy storage and inhibits enzymes that break 
down energy stores. Thus the phenotype of the cell 
is reset so the cell is optimally prepared to carry out 
energy storage functions. There has long been specu- 
lation that coordinate control of the transcription of 
genes involved in these diverse metabolic processes 
CELL BIOLOGY AND REGULATION 9 
