Lipid-Protein
Interactions
A wide
variety of diseases are results of deficient or abnormal
protein-lipid interactions. The elucidation of the
interactions between specific proteins and lipids, and
the ability to examine and manipulate biomembranes that
mimic real life systems hold the key to a better
understanding of these diseases. Our research interests
lie in the interdisciplinary area which can be termed as
"interfacial medicine". Using two-dimensional
monolayers, either at the air-water interface or
transferred onto solid substrates, and supported bilayers
as model systems, along with various microscopy and
scattering techniques, we plan to carry out fundamental
studies on the interactions between lipids and proteins
to gain insights into the biophysical aspects of these
diseases. Two diseases of particular interest are listed
below.
Lung
Surfactant System and Respiratory Distress Syndrome (RDS)
A complex mixture of lipids and proteins, known as lung
surfactant, forms monolayers at the alveolar air-water
interface. The surfactant lowers the surface tension to
near zero, and is responsible for reducing the work of
breathing. A lack of surfactant, either due to immaturity
in premature infants or disease or trauma in adults, can
result in RDS. In spite of the serious morbidity and
mortality of the disease, a firm understanding of the
role of surfactant in both normal and diseased lungs is
still lacking. My group is interested in developing a
detailed structure-function relationship for the various
components of lung surfactant. In particular, we will
examine the phase behavior of various mixtures of lung
surfactant components, as well as the interactions
between lung surfactant specific proteins and the
surrounding lipid matrix. We will explore the effect of
lung surfactant proteins on monolayer collapse dynamics,
and the effect of serum proteins on the normal
functioning of the lung surfactant. The knowledge gained
from this should lead to an understanding of the
morphological consequences of monolayer phase separation
and collapse, which is necessary for the continued
development of positive interventions for patients
suffering from RDS.
Amyloid
beta (A-beta) Peptides and Alzheimer's Disease
A-beta, a self-assembling 39-43 residue peptide generated
by the proteolytic processing of the amyloid precursor
protein, comprises the major proteinaceous component of
neuritic plaques and vascular deposits that appear in
Alzheimer¹s disease, and is implicated as one of the
causal factors in the pathology of the disease. Since the
Ab peptide fragment includes 28 residues just outside the
membrane plus the first 11-15 residues of the
transmembrane domain, it has been shown to display
properties commonly associated with surfactants. My group
is interested in understanding the aggregation of the
A-beta peptides, and in using two-dimensional thin films
(either free-standing monolayers or supported bilayers)
as "templates" to explore the possibility of
surface-induced aggregation. We plan to study various
isoforms of A-beta and examine their surface activities
and their association with model membrane systems in both
their monomeric and aggregated states. This can elucidate
the residue length dependence of the aggregation process,
and help explain why the longer A-beta isoforms may be
more intimately associated with Alzheimer's disease
pathology than their shorter counterparts. A-beta is also
known to aggregate and form fibrils, though the mechanism
involved is still not well understood. Since the rate of
this process can be adjusted by various experimental
parameters, we plan to monitor the formation process, and
characterize the structure of the fibrils formed. Our
goal is to provide a model for A-beta aggregation.
Other research interests of the group includes protein
and lipid diffusion in model membrane systems, structures
and dynamics of monolayer domains, and the manipulation
of supported bilayers via electric field.
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