Award Date


Degree Type


Degree Name

Doctor of Philosophy (PhD)


Chemistry and Biochemistry

First Committee Member

Hong Sun

Second Committee Member

Hui Zhang

Third Committee Member

Ernesto Abel-Santos

Fourth Committee Member

Laurel Raftery

Number of Pages



Acid Sphingomyelinase (ASM) is a lipid-modifying enzyme that breaks down sphingomyelin lipids into ceramide and phosphorylcholine. Genetic mutations in the human ASM gene leads to Niemann pick diseases (NPD) type A & B. In NPD type A, patients die between 1-2 years old due to severe neurological complications, while NPD type B patients live to adulthood but suffer from severe visceral organ complications. Type A is usually associated with complete inactivation of the ASM gene. The hallmark of NPD is Purkinje neuron (PN) death. PNs, the major neurons in the cerebellum part of the brain, regulate the balance and fine movement. ASM deficient mouse models were created in 1995, which showed progressive neurodegeneration of PNs; however, the underlying mechanism of PN death is not completely understood. Our lab showed that ASM homolog in C. eleganse regulates the insulin-like growth factor receptor-1 (IGF-1R)-like signaling pathway. IGF-1R is a plasma membrane receptor that belongs to the receptor tyrosine kinase (RTK) family. IGF-1R regulates different cell functions including survival, proliferation, migration, and differentiation. Also, IGF-1R signaling maintains organ homeostasis by regulating adult tissue stem differentiation. Our lab subsequently demonstrated that ASM regulates RTK signaling (including cMET and IGF-1R) in human cancer cells. Whether ASM regulates IGF-1R signaling in vivo is still unknown. To this end, we created global and conditional Asm knockout (KO) mouse models to study the function of Asm in vivo.

My data showed that Asm loss in mice recapitulated NPD type B phenotype and caused progressive Purkinje neuron death. ASM loss also reduced white adipose tissue (fat) in an age-dependent manner, which is accompanied by an accumulation of stromal cells carrying stem cell marker CD34. When adipose progenitor cells were isolated from adipose tissue, Asm loss causes reduced in vitro differentiation which is accompanied by a reduction of IGF-1R and AKT phosphorylation and activation. I have also generated an ASM conditional mouse model (cKO) where ASM is selectively inactivated in cells expressing Nestin protein. Nestin is known to be expressed in neural stem cells and mesenchymal stem cells. My preliminary data showed that ASM cKO mice had a 50% reduction in both perigonadal and subcutaneous adipose tissues. In addition, the adipose progenitor cells from the cKO mice fail to differentiate into adipocytes in vitro. These studies suggest that ASM regulates adipogenic progenitor cells in vivo and in vitro.

My studies also revealed an important role of ASM to regulate bone marrow stromal/stem cells (bMSCs). Although most studies are conducted with the isolated bMSCs in vitro, I have discovered a critical role for the IGF-1R/AKT signaling pathway in the osteogenic differentiation and transformation of bMSCs, and both can be effectively inhibited by ablation of the Asm gene.

Overall, our genetic mouse models recapitulated the Purkinje neuron loss in Niemann pick diseases and pinpointed a novel role of ASM in maintaining tissue homeostasis and integrity. Our data suggest that Asm is critical for IGF-1R signaling in the regulation of multiple stem cell compartments in adulthood, and likely in maintaining Purkinje neuron survival.


Acid Sphingomyelinase (ASM); Niemann pick diseases (NPD); Purkinje neuron (PN) death


Biochemistry | Cell Biology | Molecular Biology

File Format


File Size


Degree Grantor

University of Nevada, Las Vegas




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Available for download on Friday, August 15, 2025