SUMMARY
Alveolar tissues must maintain proper cellular organization to perform vital functions such as gas-
exchange at homeostasis and during repair. In human lungs, type-1 alveolar epithelial cells (AT1), a key cell
type that serves as a barrier and facilitates gas exchange, are extremely thin, large, and estimated to cover
95% of the surface. Aging, genetic alterations, metabolic dysregulation, and environmental exposures, all are
well recognized etiological factors in fatal lung diseases such as pulmonary fibrosis and emphysema, are
known to impair replenishment of AT1 cells after injury. Significant progress has been made in understanding
the pathways controlling differentiation of type-2 alveolar epithelial cell (AT2) into AT1s after injury. Currently
we lack a comprehensive understanding of the mechanisms regulating proper establishment and
maintenance of AT1 cellular organization (ex: thickness, area) during repair after injury and how they intersect
with age-related genetic alterations and cellular dysfunction remain elusive.
Here, we identified MAPT (microtubule associated protein, also known as Tau) as a key regulator that
is essential for AT2 to AT1 cell differentiation and AT1 cellular organization. Significantly, this co-insides with
recent genome-wide association studies that identified potential risk variants in MAPT in COPD and
pulmonary fibrosis patients. Using genetic loss of function and dysfunctional Tau mutants, our preliminary
data suggested a key role for Tau in AT1 cellular organization by regulating microtubule bundles and
mitochondrial dynamics during lung repair in young and aged lungs. We hypothesize that Tau mediated
microtubule bundling and mitochondrial dynamics control proper differentiation of AT2s into large
and thin AT1 cells and that Tau mutations or its age-associated abnormal phosphorylation impairs
mitochondrial dynamics, mitophagy, and function during alveolar repair after injury.
The major goals of this proposal are: In Aim1, we will test the requirement of Tau and consequences
of expression of a human relevant pathological form of Tau in alveolar stem cell mediated regeneration. In
Aim2, we will test the hypothesis that genetic loss or age associated dysfunctional Tau impairs alveolar
epithelial cell microtubule dynamics and mitochondrial remodeling, and function. We will use genetic loss of
function, tubulin and mitochondrial reporter mouse models, confocal and electron microscopy, pulmonary
function tests, RNA-seq, co-cultures, live imaging, metabolic assays to assess cellular organization,
microtubule and mitochondrial dynamics during lung regeneration in young and aged mice following Tau
modulation. The outcomes from the proposed studies will have broader impact on lung regenerative medicine
and will form the basis for development of therapeutics to lung diseases.
