Hormonal, Metabolic, and Signaling Interactions in PAH

Project 1: This project will work to understand why women are affected by pulmonary arterial
hypertension (PAH) so much more often than men. This observation is true in heritable,
idiopathic and associated forms of PAH. While males and females have some similar hormone
levels, certain hormones exist at higher levels in each gender. For example, estrogen levels
are much higher in females, and thus seemed the most sensible place to start looking for
differences that may be affecting disease. In a small, early study of our heritable patients,
we found differences in how patients break down estrogens as compared to healthy control
subjects. Now, we want to confirm that what we found is true in a much larger group of
patients that includes idiopathic and associated forms of PAH. We will also look to see if
testosterone and other androgenic hormones are somehow protective for males. If the
observation holds true in the larger group of patients, then we may try to "fix" the hormone
imbalance in a mouse model of PAH with a drug therapy, and see if it helps improve the mouse
pulmonary hypertension without bad side effects to the animals. If the animal drug studies
work, then we may be able to try this drug in patients to see if it will work as a human
treatment.

Project 2: Despite major advances in understanding PAH in recent decades, safe, effective and
tolerable therapies remain elusive. The metabolic syndrome (central obesity, insulin
resistance, high blood pressure and hyperlipidemia—fats in the blood) has been implicated in
PAH. Treating the downstream consequences of insulin resistance in the pulmonary vasculature
is a new approach to effective intervention against this highly mortal disease. This project
will study the role of insulin resistance in pulmonary arterial hypertension and determine if
therapies to treat insulin resistance will improve pulmonary arterial hypertension.

Project 3: In Project 3, we are working on the theory that PAH can be treated by fixing
cell-cell junctions in blood vessels with a drug called recombinant ACE2(angiotensin
converting enzyme 2). This is the only approach so far that has worked to reverse disease in
mouse models of heritable PAH, but we need to better understand how it is working and make
sure it has long term safety in animal models before starting human trials, hopefully within
a few years. Definition: Cell-cell junctions-all of our organs and body structures are made
from cells. Normally, these cells (think of a balloon filled with water) line up right next
to each other so that the cell membranes touch each other. Materials can flow from one cell
to the next. In PAH patients it is believed that the cells in the linings of the small
arteries are not able to line up together as they should.

Inclusion Criteria:

Project 1

Inclusion:

1. Diagnosis of IPAH (idiopathic pulmonary arterial hypertension), HPAH (heritable
pulmonary arterial hypertension), or APAH (associated pulmonary arterial
hypertension), family members of affected persons

2. Age 0-90, age 12-90 for skin biopsy

Exclusion:

1. Other diagnosis

2. Age greater than 90, age less than 12 or greater than 90 for skin biopsy

Project 2

Inclusion:

1. Diagnosis of IPAH, HPAH, or APAH, family members of affected persons

2. 0-90

3. Subjects with reasonably easy access to clinic for blood collection and other testing

4. Subject able to tolerate fasting state prior to sample collection and EndoPAT
(endothelial function assessment) testing

Exclusion:

1. Other diagnosis

2. 0-90

3. Subjects with difficulty reaching clinic for blood collection and other testing

4. Subjects unable to tolerate fasting state

Project 3

Inclusion:

1. Diagnosis of IPAH, HPAH, or APAH, family members of affected persons

2. 7-90

Exclusion:

1. Other diagnosis

2. Age less than 7 or greater than 90

Exclusion Criteria: