Publication Date

2019-04-11

Availability

Open access

Embargo Period

2019-04-11

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Neuroscience (Medicine)

Date of Defense

2019-03-20

First Committee Member

Daniel J. Liebl

Second Committee Member

Coleen M. Atkins

Third Committee Member

Thomas J. Sick

Fourth Committee Member

Daniel G. Isom

Abstract

Herein is described an effort to understand if the intracellular transmembrane protein, TMEM97, participates in cell death cascades following traumatic brain injury (TBI). TMEM97 is an endoplasmic-reticulum (ER) resident protein shown to interact with the lysosomal Niemann-Pick disease type C (NPC) intracellular cholesterol transporter 1 (NPC1) under metabolic sterol stress. To commence experimentation, an in vitro cell stress paradigm was employed to assess how increasing TMEM97 levels affect cell survival following metabolic and sterol stress. To characterize the in vivo expression profile and effects of TMEM97 deletion on cell survival outcome, we generated germ-line TMEM97-/- mice harboring a LacZ reporter gene, and performed sham and controlled cortical impact (CCI) injuries and assessed cell survival by blinded, unbiased stereological assessment. Further, a novel small molecule antagonist of TMEM97, DKR-1677, was systematically administered to sham and CCI injured PLP-GFP mice, and its neuroprotective effect was assessed by quantifying neurons and oligodendrocytes in the injury penumbra and underlying white matter tracts. It was concluded that increased TMEM97 expression resulted in increased cell death in our in vitro paradigm and that TMEM97-/- results in increased survival of neural cell populations that would otherwise express TMEM97 in mice. Additionally, a 7-day intraperitoneal (IP) administration paradigm of DKR-1677 resulted in increased survival trends of both neurons and oligodendrocytes in the cortical penumbra compared to vehicle treatment. In sum, our in vitro and in vivo evidence indicate that TMEM97 signaling is deleterious to cell survival following injury-induced stress.

Keywords

Traumatic Brain Injury; TMEM97; Neuroprotection

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