Gnas inactivation in heterotopic ossification / Niambi Sakile Brewer.

Format:

Book

Thesis/Dissertation

Author/Creator:

Brewer, Niambi Sakile, author.

Contributor:

Shore, Eileen M., degree supervisor.

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

Language:

English

Subjects (All):

Cellular biology.

Cell and molecular biology--Penn dissertations.

Penn dissertations--Cell and molecular biology.

Local Subjects:

Cellular biology.

Cell and molecular biology--Penn dissertations.

Penn dissertations--Cell and molecular biology.

Genre:

Academic theses.

Physical Description:

1 online resource (138 pages)

Contained In:

Dissertations Abstracts International 82-12B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2021.

Language Note:

English

System Details:

Mode of access: World Wide Web.

text file

Summary:

Heterotopic ossification (HO), the formation of bone outside of the skeleton, occurs in response to severe trauma and in rare genetic diseases such as progressive osseous heteroplasia (POH). In POH, which is caused by inactivation of GNAS, a gene that encodes the alpha stimulatory subunit of G proteins (Gαs), HO typically initiates within subcutaneous soft tissues before progressing to deeper connective tissues. To mimic POH, we used conditional Gnas-null mice which form HO in subcutaneous tissues upon Gnas inactivation. In response to Gnas inactivation, we determined that prior to detection of heterotopic bone, dermal adipose tissue changed dramatically, with progressively decreased adipose tissue volume and increased density of extracellular matrix over time. Upon depletion of the adipose tissue, heterotopic bone progressively formed in those locations. Through implant studies of adipose stromal cells, we found that mutant cells in a Gnas-null tissue environment induced a robust HO response while little/no HO was detected in control hosts. Additionally, a Gnas-null tissue environment appeared to support the recruitment of control cells to heterotopic bone, although control cell implants were associated with less HO formation compared to mutant cells. Our data support that Gnas inactivation alters the tissue microenvironment to influence mutant and wild-type progenitor cells to contribute to HO formation. Simultaneously, Gnas inactivation in ASCs leads to a potential misinterpretation of soft substrates, which can influence the osteogenic phenotype. While POH is a rare genetic disorder, this model helps to also provide an understanding of the processes of non-genetic HO and can inform us of potential targets for intervention and preventative therapeutics.

Notes:

Source: Dissertations Abstracts International, Volume: 82-12, Section: B.

Advisors: Shore, Eileen M.; Committee members: Rebecca Wells; Patrick Seale; Marisa Bartolomei; Thomas Jongens.

Department: Cell and Molecular Biology.

Ph.D. University of Pennsylvania 2021.

Local Notes:

School code: 0175

ISBN:

9798738642395

Access Restriction:

Restricted for use by site license.

This item is not available from ProQuest Dissertations & Theses.

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