Cardiac Effects of Huntington's Disease in Murine Models / Daniel David Child.

Format:

Book

Thesis/Dissertation

Author/Creator:

Child, Daniel David, author.

Contributor:

Davidson, Beverly L., degree supervisor.

University of Pennsylvania. Department of Cell and Molecular Biology, degree granting institution.

Language:

English

Subjects (All):

Cellular biology.

Genetics.

Medicine.

Cell and molecular biology--Penn dissertations.

Penn dissertations--Cell and molecular biology.

Local Subjects:

Cellular biology.

Genetics.

Medicine.

Cell and molecular biology--Penn dissertations.

Penn dissertations--Cell and molecular biology.

Genre:

Academic theses.

Physical Description:

1 online resource (150 pages)

Contained In:

Dissertations Abstracts International 81-02B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2019.

Language Note:

English

System Details:

Mode of access: World Wide Web.

text file

Summary:

Huntington's disease (HD) is an autosomal dominant disease known for its severe neurologic phenotype. However, the causative protein in HD, mutant huntingtin (mHTT), is widely expressed across tissue types and may have profound consequences for peripheral organs. Notably, heart disease is the second leading cause of death in HD patients, but if or how cardiac mHTT expression causes pathology is still unknown. Here, I characterize the cardiac phenotype in two HD mouse models and show that dysregulated mTORC1 activity is a key underlying mechanism. I show that normal heart growth is limited in HD mouse models, with mass regulated independent of systemic changes. Additionally, cardiac mTORC1 activity is decreased in HD mice starting at a presymptomatic time point in a manner that requires cardiac mHTT expression. The impaired activity results from decreased PI3K/Akt/mTOR signaling at early time points and Rheb mislocalization at later disease stages. As a result of mTORC1 dysregulation, HD mice have increased mortality, inability to hypertrophy, and increased pathologic changes in response to stress. Notably, this phenotype is reversed in HD mice with exogenously activated mTORC1. Thus, I propose that mHTT expression in HD hearts dysregulates mTORC1 and leads to increased mortality with heart disease.

Notes:

Source: Dissertations Abstracts International, Volume: 81-02, Section: B.

Advisors: Davidson, Beverly L.; Committee members: Meera Sundaram; Zoltan Arany; Vera Krymskaya; Francis McGowan.

Department: Cell and Molecular Biology.

Ph.D. University of Pennsylvania 2019.

Local Notes:

School code: 0175

ISBN:

9781085568494

Access Restriction:

Restricted for use by site license.

This item must not be sold to any third party vendors.