자료유형  

 학위논문

Control Number  

0017161728

International Standard Book Number  

9798382776460

Dewey Decimal Classification Number  

574

Main Entry-Personal Name  

Ma, Chanthia C.

Publication, Distribution, etc. (Imprint  

[S.l.] : Harvard University., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

131 p.

General Note  

Source: Dissertations Abstracts International, Volume: 85-12, Section: B.

General Note  

Advisor: Walsh, Christopher A.

Dissertation Note  

Thesis (Ph.D.)--Harvard University, 2024.

Summary, Etc.  

요약Various recent studies into the genomics of human disease have focused on somatic mutations. Unlike germline mutations, somatic mutations arise post-conception in a population of cells or individual cells of the body. In other words, they are generally not passed on to future generations as they are not shared by all cells of the parent (including the gonadal cells). The mutations incurred can be unique to one cell, which are deemed "private" somatic mutations, or can be transmitted in the setting of clonal expansion, deemed "clonal" somatic mutations. While somatic mutations are well known as drivers of cancer, somatic mutations are increasingly implicated in a variety of non-neoplastic diseases, including neurodegenerative diseases.Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease that results from a history of mild repetitive head impact (mRHI) across decades, seen in individuals with this environmental exposure such as American football players, boxers, and military veterans. The disease begins with focal lesions at the sites of damage, but progresses to widespread tissue damage that, in late stage CTE patients, causes severe cognitive impairment and other detrimental neuropsychiatric manifestations. CTE is currently only diagnosable by postmortem neuropathological examination. Unlike diseases where the origin of disease may already be embedded in patient DNA or arise from a myriad of factors, the seeds of neurodegenerative spread in CTE can seemingly be traced to one external variable - the history of mRHI. This history transforms an ostensibly healthy, neurotypical brain into a severely degenerated brain. My thesis focuses on how this history of external trauma, translated into alterations at the molecular level of the genome, can be revealed through the study of both private and clonal somatic mutations and what the patterns extracted from these mutational changes can tell us about the causative agents driving the progression of disease pathology and neurodegenerative spread in CTE, and perhaps neurodegeneration in general.I first present our work studying the burden and mutational patterns of single nucleotide variants (SNVs) and insertion-deletions (indels), two types of private somatic mutations. We found a significant variation in somatic mutational burden in CTE individuals as compared with neurotypical controls as well as compared with a cohort of RHI individuals with a similar history of mRHI but no CTE diagnosis. Unique mutational patterns implicate distinct molecular pathways involved in double-stranded and single-stranded genomic alterations. Finally, I introduce my second project studying the prevalence of clonal somatic mutations, particularly those involved in pathogenic clonal expansion, and how their alterations in CTE give us further insight into the mechanisms of neurodegenerative spread. Using novel cutting-edge techniques in genomics and molecular biology, I study the somatic genetic alterations in an understudied neurodegenerative disease induced by external trauma.

Subject Added Entry-Topical Term  

Biology.

Subject Added Entry-Topical Term  

Neurosciences.

Subject Added Entry-Topical Term  

Genetics.

Subject Added Entry-Topical Term  

Cellular biology.

Subject Added Entry-Topical Term  

Pathology.

Index Term-Uncontrolled  

Chronic Traumatic Encephalopathy

Index Term-Uncontrolled  

Neurodegeneration

Index Term-Uncontrolled  

Somatic mutations

Index Term-Uncontrolled  

Single nucleotide variants

Index Term-Uncontrolled  

Genomic alterations

Added Entry-Corporate Name  

Harvard University Medical Sciences

Host Item Entry  

Dissertations Abstracts International. 85-12B.

Electronic Location and Access  

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Control Number  

joongbu:654789