Role of PIKfyve in platelet lysosomal homeostasis.

Format:

Book

Thesis/Dissertation

Author/Creator:

Min, Sang Hee, author.

Contributor:

Abrams, Charles S., degree supervisor.

University of Pennsylvania. Cell and Molecular Biology.

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 (120 pages)

Contained In:

Dissertation Abstracts International 76-05B(E).

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor, MI : ProQuest, 2014.

System Details:

Mode of access: World Wide Web.

text file

Summary:

PIKfyve is a lipid kinase that is essential for the synthesis of phosphatidylinositol-3,5-bisphosphate [PtdIns(3,5)P2], and for the regulation of membrane dynamics within the endolysosomal system in mammals. Depletion of intracellular pools of PtdIns(3,5)P2 in humans and in mice is associated with neurodegeneration and early lethality. However, the biological role of PtdIns(3,5)P2 in non-neural tissues is not well understood. Platelets are hematopoietic cells that function in a variety of physiological responses. Essential to many of these functions is the activation-dependent release of effectors from distinct storage granules - alpha granules, dense granules, and lysosomes - that derive from the endolysosomal system. In this work, we show that platelet-specific ablation of the PIKfyve gene in mice results in accelerated arterial thrombosis, but also unexpectedly to multiorgan defects that impair development, body mass, fertility, and survival by inducing inappropriate inflammatory responses characterized by macrophage accumulation in multiple tissues. Platelet depletion in vivo significantly impairs the progression of multiorgan defects in these mice, confirming that these defects reflect a platelet-specific process. Although PIKfyve-null platelets generate and release normal amounts of alpha granule and dense granule contents, they develop defective maturation and excessive storage of lysosomal enzymes, which are released upon platelet activation. Remarkably, impairing the secretion of lysosomes from PIKfyve-deficient platelets in vivo significantly attenuates the multiorgan defects in mice, suggesting that platelet lysosome secretion contributes to pathogenesis. Together, these results demonstrate that PIKfyve is an essential regulator for the biogenesis of platelet lysosomes, and highlight the previously unrecognized and important pathological contributions of platelet lysosomes in inflammation, arterial thrombosis, and macrophage biology.

Notes:

Source: Dissertation Abstracts International, Volume: 76-05(E), Section: B.

Adviser: Charles S. Abrams.

Department: Cell and Molecular Biology.

Thesis Ph.D. University of Pennsylvania 2014.

Local Notes:

School code: 0175.

ISBN:

9781321479850

Access Restriction:

Restricted for use by site license.