Characterization and Development of a New Animal Model of Pulmonary Hypertension

DESCRIPTION (provided by applicant): Currently, a major obstacle facing basic pulmonary hypertension (PH) and right ventricular (RV) dysfunction/failure research is the lack of good, truly representative animal models for either of these 2 very serious human disorders. As a result, the efforts of investigators' to probe the cellular and molecular basis(es) for the development of these potentially life threatening diseases are seriously stymied. Recently, our laboratory identified an emerging line of Spontaneously Hypertensive Heart Failure (SHHF) rats that present with PH and massive, early (~ 2 months), RV hypertrophy - RV hypertrophy that appears to precede and vastly exceed that observed in the left ventricle. Preliminary evidence suggests that the traits of early onset of PH and RV hypertrophy are heritable in this emerging line of SHHF rats (henceforth designated as SHHF-PH). The SHHF-PH rat may represent a novel and exciting model of spontaneous PPH and RV dysfunction/failure of great value and importance to basic and applied human biomedical research. The overall objective of this proposal is to carefully examine, rigorously test and effectively demonstrate the potential value of a new experimental rodent model, a model that appears to more closely/effectively parallel key disease elements found to be associated with human pulmonary hypertension, to an extent not currently possible using other animal models. The specific objectives of the project are: 1. Characterize key pulmonary structural abnormalities and biochemical and gene expression changes that occur in the SHHF-PH rat throughout the development of PH; 2. Characterize key functional, biochemical and morphological RV and LV abnormalities and gene expression changes that occur in the SHHF-PH rat throughout the development of PH; 3. Compare the key functional, morphological and biochemical differences and alterations in gene expression found in the SHHF-PH rat to the only other genetic rat model of PH the FHR and the commonly used monocrotaline-induced PH rat; 4. Characterize the lineage and heritability of the RV hypertrophy and PH traits observed in the emerging line of SHHF-PH rats and establish and expand the new line. Once adequately tested and demonstrated to represent a superior research platform, the SHHF-PH rats would be licensed to a commercial rodent breeder. In this way an improved animal model - the SHHF-PH rat - will be made readily accessible to any and all investigators seeking to more completely understand the pathobiology associated with human PH and RV dysfunction and/or those seeking to develop more effective treatment strategies to combat these diseases. At the present time, a major obstacle facing basic pulmonary hypertension (PH) and right ventricular (RV) dysfunction/failure research is the lack of good, truly representative animal models for either of these 2 very serious human disorders. The overall objective of this proposal is to carefully examine, rigorously test and effectively demonstrate the potential value of a new experimental rodent model, a model that appears to more closely/effectively parallel key disease elements found to be associated with human pulmonary hypertension and RV dysfunction, to an extent not currently possible using other animal models - specifically, the SHHF-PH rat.